Hexahydro-cyclooctyl pyrazole cannabinoid modulators

ABSTRACT

This invention is directed to a hexahydro-cyclooctyl pyrazole cannabinoid modulator compound of formula (I): 
                         
and a method for use in treating, ameliorating or preventing a cannabinoid receptor mediated syndrome, disorder or disease.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a divisional application of U.S. applicationSer. No. 11/525,573 filed Sep. 22, 2006 now U.S. Pat. No. 7,851,498which claims the benefits of the filing of U.S. Provisional ApplicationNo. 60/719,884, filed Sep. 23, 2005. The complete disclosures of theaforementioned related patent applications are hereby incorporatedherein by reference for all purposes.

FIELD OF THE INVENTION

This invention is directed to hexahydro-cyclooctyl pyrazole cannabinoid(CB) modulator compounds and a method for use in treating, amelioratingor preventing a cannabinoid receptor mediated syndrome, disorder ordisease.

BACKGROUND OF THE INVENTION

Before the discovery of the cannabinoid CB1 and CB2 receptors, the termcannabinoid was used to describe the biologically active components ofcannabis sativa, the most abundant of which aredelta-9-tetrahydrocannabinol (THC) and cannabidiol.

THC is a moderately potent partial agonist of the CB1 and CB2 receptorsand is considered the “classical cannabinoid,” a term now used to referto other analogues and derivatives that are structurally related to thetricyclic dibenzopyran THC core. The term “nonclassical cannabinoid”refers to cannabinoid agonists structurally related to cannabidiol.

Pharmacological investigations have concentrated on selective CBreceptor modulators of the pyrazole structural class, which include SR141716A (the monohydrochloride salt of SR 141716) and SR 144528.

Pyrazole cannabinoid modulators are one among the many differentstructural classes which have aided the development of CB pharmacology,have helped to determine the biological effects mediated by thecannabinoid receptors, will lead to further refinement of currentcompounds and will be a source of new chemical classes in the future.

Certain compounds (including SR 141716, SR 144528 and the like) thatwere originally classified as selective antagonists are now consideredto act as “inverse agonists” rather than pure antagonists. Inverseagonists have the ability to decrease the constitutive level of receptoractivation in the absence of an agonist instead of only blocking theactivation induced by agonist binding at the receptor. The constitutiveactivity of CB receptors has important implications since there is alevel of continuous signaling by both CB1 and CB2 even in the absence ofan agonist. For example, SR 141716A increases CB1 protein levels andsensitizes cells toward agonist action, thus indicating that inverseagonists may be another class of ligands used to modulate theendocannabinoid system and the downstream signaling pathways activatedby CB receptors.

PCT Application WO2006/030124 describes pyrazole derivatives as CB1 orCB2 receptor agonists.

Advances in the synthesis of CB and cannabimimetic ligands havefurthered the development of receptor pharmacology and provided evidencefor the existence of additional cannabinoid receptor sub-types. However,there remains an ongoing need for the identification and development ofCB1 or CB2 receptor cannabinoid modulators for the treatment of avariety of CB receptor modulated syndromes, disorders and diseases.

DETAILED DESCRIPTION OF THE INVENTION

This invention is directed to a compound of formula (I):

or a salt, isomer, prodrug, metabolite or polymorph thereof wherein

-   the dashed lines between positions 2-3 and positions 3a-9a in    formula (I) represent locations for each of two double bonds present    when X₁R₁ is present;-   the dashed lines between positions 3-3a and positions 9a-1 in    formula (I) represent locations for each of two double bonds present    when X₂R₂ is present;-   the dashed line between position 9 and X₄R₄ in formula (I)    represents the location for a double bond;-   X₁ is absent or lower alkylene;-   X₂ is absent or lower alkylene;-   wherein only one of X₁R₁ and X₂R₂ are present;-   X₃ is absent, lower alkylene, lower alkylidene or —NH—;-   when the dashed line between position 9 and X₄R₄ is absent, X₄ is    absent or lower alkylene;-   when the dashed line between position 9 and X₄R₄ is present, X₄ is    absent;-   X₅ is absent or lower alkylene;-   R₁ is selected from hydrogen, alkyl (optionally substituted at one    or more positions by halogen, hydroxy or lower alkoxy), lower    alkyl-sulfonyl, aryl, C₃-C₁₂ cycloalkyl or heterocyclyl, wherein    aryl, C₃-C₁₂ cycloalkyl or heterocyclyl is each optionally    substituted at one or more positions by halogen, aminosulfonyl,    lower alkyl-aminosulfonyl, alkyl (optionally substituted at one or    more positions by halogen, hydroxy or lower alkoxy), hydroxy or    alkoxy (optionally substituted at one or more positions by halogen    or hydroxy);-   R₂ is selected from hydrogen, alkyl (optionally substituted at one    or more positions by halogen, hydroxy or lower alkoxy), lower    alkyl-sulfonyl, aryl, C₃-C₁₂ cycloalkyl or heterocyclyl, wherein    aryl, C₃-C₁₂ cycloalkyl or heterocyclyl is each optionally    substituted at one or more positions by halogen, aminosulfonyl,    lower alkyl-aminosulfonyl, alkyl (optionally substituted at one or    more positions by halogen, hydroxy or lower alkoxy), hydroxy or    alkoxy (optionally substituted at one or more positions by halogen    or hydroxy);-   R₃ is —C(O)—Z₁(R₆), —SO₂—NR₇—Z₂(R₈) or —C(O)—NR₉—Z₃(R₁₀);-   when the dashed line between position 9 and X₄R₄ is absent, X₄ is    absent or lower alkylene and R₄ is hydrogen, hydroxy, lower alkyl,    lower alkoxy, halogen, aryl, C₃-C₁₂ cycloalkyl or heterocyclyl,    wherein aryl, C₃-C₁₂ cycloalkyl or heterocyclyl is each optionally    substituted at one or more positions by hydroxy, oxo, lower alkyl    (optionally substituted at one or more positions by halogen, hydroxy    or lower alkoxy), lower alkoxy (optionally substituted at one or    more positions by halogen or hydroxy) or halogen;-   when the dashed line between position 9 and X₄R₄ is present, X₄ is    absent and R₄ is CH-aryl or CH-heterocyclyl, wherein aryl or    heterocyclyl is each optionally substituted at one or more positions    by hydroxy, oxo, lower alkyl, lower alkoxy or halogen;-   R₅ is absent, hydroxy, halogen, amino, aminoalkyl, alkyl (optionally    substituted at one or more positions by halogen, hydroxy or lower    alkoxy), alkoxy (optionally substituted at one or more positions by    halogen or hydroxy), carboxy, carbonylalkoxy, carbamoyl,    carbamoylalkyl, aryl, aryloxy, arylalkoxy or heterocyclyl;-   R₆ is aryl, C₃-C₁₂ cycloalkyl or heterocyclyl, wherein aryl, C₃-C₁₂    cycloalkyl or heterocyclyl is each optionally substituted by one or    more hydroxy, oxo, halogen, amino, aminoalkyl, alkyl (optionally    substituted at one or more positions by halogen, hydroxy or lower    alkoxy), alkoxy (optionally substituted at one or more positions by    halogen or hydroxy), carboxy, carbonylalkoxy, carbamoyl,    carbamoylalkyl, aryl, aryloxy, arylalkoxy or heterocyclyl;-   R₇ is hydrogen or lower alkyl;-   R₈ is aryl, C₃-C₁₂ cycloalkyl or heterocyclyl, wherein aryl, C₃-C₁₂    cycloalkyl or heterocyclyl is each optionally substituted by one or    more hydroxy, oxo, halogen, amino, aminoalkyl, alkyl (optionally    substituted at one or more positions by halogen, hydroxy or lower    alkoxy), alkoxy (optionally substituted at one or more positions by    halogen or hydroxy), carboxy, carbonylalkoxy, carbamoyl,    carbamoylalkyl, aryl, aryloxy, arylalkoxy or heterocyclyl;-   R₉ is hydrogen or lower alkyl;-   R₁₀ is aryl, C₃-C₁₂ cycloalkyl or heterocyclyl, wherein aryl, C₃-C₁₂    cycloalkyl or heterocyclyl is each optionally substituted by one or    more hydroxy, oxo, halogen, amino, aminoalkyl, alkyl (optionally    substituted at one or more positions by halogen, hydroxy or lower    alkoxy), alkoxy (optionally substituted at one or more positions by    halogen or hydroxy), carboxy, carbonylalkoxy, carbamoyl,    carbamoylalkyl, aminosulfonyl, lower alkyl-aminosulfonyl, aryl,    aryloxy, arylalkoxy or heterocyclyl;-   Z₁ and Z₂ is each absent or alkyl; and,-   Z₃ is absent, —NH—, —SO₂— or alkyl (wherein alkyl is optionally    substituted at one or more positions by halogen, hydroxy, lower    alkyl, lower alkoxy, carboxy or carbonylalkoxy).

An example of the present invention is a compound of formula (I) or asalt, isomer, prodrug, metabolite or polymorph thereof wherein X₁ isabsent or lower alkylene; and, R₁ is selected from hydrogen, alkyl(optionally substituted at one or more positions by halogen, hydroxy orlower alkoxy), aryl, C₃-C₁₂ cycloalkyl or heterocyclyl, wherein aryl,C₃-C₁₂ cycloalkyl or heterocyclyl is each optionally substituted at oneor more positions by halogen, alkyl (optionally substituted at one ormore positions by halogen, hydroxy or lower alkoxy), hydroxy or alkoxy(optionally substituted at one or more positions by halogen or hydroxy).

An example of the present invention is a compound of formula (I) or asalt, isomer, prodrug, metabolite or polymorph thereof wherein X₁ isabsent; and, R₁ is selected from aryl or C₃-C₁₂ cycloalkyl, wherein arylis optionally substituted at one or more positions by halogen.

An example of the present invention is a compound of formula (I) or asalt, isomer, prodrug, metabolite or polymorph thereof wherein R₃ is—C(O)—Z₁(R₆), —SO₂—NH—Z₂(R₈) or —C(O)—NH—Z₃(R₁₀).

An example of the present invention is a compound of formula (I) or asalt, isomer, prodrug, metabolite or polymorph thereof wherein R₃ is—C(O)—Z₁(R₆); X₃ is absent, lower alkylene, lower alkylidene or —NH—; Z₁is absent or alkyl; and, R₆ is aryl, C₃-C₁₂ cycloalkyl or heterocyclyl,wherein aryl, C₃-C₁₂ cycloalkyl or heterocyclyl is each optionallysubstituted by one or more hydroxy, oxo, halogen, amino, aminoalkyl,alkyl (optionally substituted at one or more positions by halogen,hydroxy or lower alkoxy), alkoxy (optionally substituted at one or morepositions by halogen or hydroxy), carboxy, carbonylalkoxy, carbamoyl,carbamoylalkyl, aryl, aryloxy, arylalkoxy or heterocyclyl.

An example of the present invention is a compound of formula (I) or asalt, isomer, prodrug, metabolite or polymorph thereof wherein R₃ is—C(O)—Z₁(R₆); X₃ is absent; Z₁ is absent; and, R₆ is heterocyclyl.

An example of the present invention is a compound of formula (I) or asalt, isomer, prodrug, metabolite or polymorph thereof wherein R₃ is—C(O)—NR₉—Z₃(R₁₀); X₃ is absent, lower alkylene, lower alkylidene or—NH—; R₉ is hydrogen or lower alkyl; Z₃ is absent, —NH—, —SO₂— or alkyl(wherein alkyl is optionally substituted at one or more positions byhalogen, hydroxy, lower alkyl, lower alkoxy, carboxy or carbonylalkoxy);and, R₁₀ is aryl, C₃-C₁₂ cycloalkyl or heterocyclyl each optionallysubstituted by one or more hydroxy, oxo, halogen, amino, aminoalkyl,alkyl (optionally substituted at one or more positions by halogen,hydroxy or lower alkoxy), alkoxy (optionally substituted at one or morepositions by halogen or hydroxy), carboxy, carbonylalkoxy, carbamoyl,carbamoylalkyl, aminosulfonyl, lower alkyl-aminosulfonyl, aryl, aryloxy,arylalkoxy or heterocyclyl.

An example of the present invention is a compound of formula (I) or asalt, isomer, prodrug, metabolite or polymorph thereof wherein R₃ is—C(O)—NH—Z₃(R₁₀); X₃ is absent; Z₃ is absent, —NH— or alkyl (whereinalkyl is optionally substituted at one or more positions by halogen,hydroxy, lower alkyl, lower alkoxy, carboxy or carbonylalkoxy); and, R₁₀is aryl, C₃-C₁₂ cycloalkyl or heterocyclyl each optionally substitutedby one or more hydroxy, oxo, halogen, amino, aminoalkyl, alkyl(optionally substituted at one or more positions by halogen, hydroxy orlower alkoxy), alkoxy, carboxy, carbonylalkoxy, aryl or heterocyclyl.

An example of the present invention is a compound of formula (I) or asalt, isomer, prodrug, metabolite or polymorph thereof wherein R₃ is—C(O)—NH—Z₃(R₁₀); X₃ is absent; Z₃ is absent or alkyl; and, R₁₀ isC₃-C₁₂ cycloalkyl optionally substituted by one or more hydroxy, oxo,halogen, amino, aminoalkyl, alkyl (optionally substituted at one or morepositions by halogen, hydroxy or lower alkoxy), alkoxy, carboxy,carbonylalkoxy, aryl or heterocyclyl.

An example of the present invention is a compound of formula (I) or asalt, isomer, prodrug, metabolite or polymorph thereof wherein R₃ is—C(O)—NH—Z₃(R₁₀); X₃ is absent; Z₃ is absent or alkyl; and, R₁₀ isC₃-C₁₂ cycloalkyl optionally substituted by one or more alkyl orcarbonylalkoxy.

An example of the present invention is a compound of formula (I) or asalt, isomer, prodrug, metabolite or polymorph thereof wherein R₃ is—C(O)—NH—Z₃(R₁₀); X₃ is absent; Z₃ is absent, —NH— or alkyl (whereinalkyl is optionally substituted at one or more positions by halogen,hydroxy, lower alkyl, lower alkoxy, carboxy or carbonylalkoxy); and, R₁₀is aryl optionally substituted by one or more hydroxy, oxo, halogen,amino, aminoalkyl, alkyl (optionally substituted at one or morepositions by halogen, hydroxy or lower alkoxy), alkoxy, carboxy,carbonylalkoxy, aryl or heterocyclyl.

An example of the present invention is a compound of formula (I) or asalt, isomer, prodrug, metabolite or polymorph thereof wherein R₃ is—C(O)—NH—Z₃(R₁₀); X₃ is absent; Z₃ is absent, —NH— or alkyl; and, R₁₀ isaryl optionally substituted by one or more halogen.

An example of the present invention is a compound of formula (I) or asalt, isomer, prodrug, metabolite or polymorph thereof wherein R₃ is—C(O)—NH—Z₃(R₁₀); X₃ is absent; Z₃ is absent or alkyl (wherein alkyl isoptionally substituted at one or more positions by halogen, hydroxy,lower alkyl, lower alkoxy, carboxy or carbonylalkoxy); and, R₁₀ isheterocyclyl optionally substituted by one or more alkyl.

An example of the present invention is a compound of formula (I) or asalt, isomer, prodrug, metabolite or polymorph thereof wherein thedashed line between position 9 and X₄R₄ is absent; X₄ is absent; and, R₄is hydrogen.

An example of the present invention is a compound of formula (I) or asalt, isomer, prodrug, metabolite or polymorph thereof wherein thedashed line between position 9 and X₄R₄ is present, X₄ is absent and R₄is CH-aryl optionally substituted on aryl at one or more positions byhalogen.

An example of the present invention is a compound of formula (I) or asalt, isomer, prodrug, metabolite or polymorph thereof wherein X₅ isabsent and R₅ is absent.

An example of the present invention is a compound of formula (Ia):

or a salt, isomer, prodrug, metabolite or polymorph thereof wherein X₁is absent; X₃ is absent; when the dashed line between position 9 andX₄R₄ is absent, X₄ is absent and R₄ is hydrogen; when the dashed linebetween position 9 and X₄R₄ is present, X₄ is absent and R₄ is CH-aryl,wherein aryl is optionally substituted at one or more positions byhalogen; R₁ is selected from aryl or C₃-C₁₂ cycloalkyl, wherein aryl isoptionally substituted at one or more positions by halogen; R₃ is—C(O)—Z₁(R₆) or —C(O)—NH—Z₃(R₁₀); R₆ is heterocyclyl; R₁₀ is aryl,C₃-C₁₂ cycloalkyl or heterocyclyl, wherein aryl or C₃-C₁₂ cycloalkyl iseach optionally substituted by one or more halogen, alkyl orcarbonylalkoxy; Z₁ is absent; and, Z₃ is absent, —NH— or alkyl.

An example of the present invention is a compound of formula (Ia) or asalt, isomer, prodrug, metabolite or polymorph thereof wherein X₁R₁,X₃R₃ and X₄R₄ are dependently selected from

Cpd X₁R₁ X₃R₃ X₄R₄ 1 cyclohexyl C(O)NH-1,3,3-(CH₃)₃- Hbicyclo[2.2.1]hept-2-yl 2 cyclohexyl C(O)NH—CH₂-adamantan- H 1-yl 3cyclopentyl C(O)NH—CH₂-adamantan- H 1-yl 4 cyclohexylC(O)NH-2-CO₂CH₂CH₃- H bicyclo[2.2.1]hept-2-yl 5 cyclopentylC(O)NH—CH(CH₃)- H adamantan-1-yl 6 cyclohexyl C(O)NH—CH(CH₃)- Hadamantan-1-yl 7 cyclopentyl C(O)NH-1,3,3-(CH₃)₃- Hbicyclo[2.2.1]hept-2-yl 8 cyclobutyl C(O)NH-1,3,3-(CH₃)₃- Hbicyclo[2.2.1]hept-2-yl 9 cyclobutyl C(O)NH—CH₂-adamantan- H 1-yl 10cyclobutyl C(O)NH—CH(CH₃)- H adamantan-1-yl 11 2,4-Cl₂-phenylC(O)NHNH-(2,4-Cl₂)-phenyl (E)-4-F-benzylidene 12 2,4-Cl₂-phenylC(O)NH—(R—CH)(phenyl)- (E)-4-F-benzylidene CH₃ 13 2,4-Cl₂-phenylC(O)NH—(R—CH)(pyridin- (E)-4-F-benzylidene 2-yl)-CH₃ 14 2,4-Cl₂-phenylC(O)-piperidin-1-yl (E)-4-F-benzylidene 15 2,4-Cl₂-phenylC(O)NH—(S—CH)(phenyl)- (E)-4-F-benzylidene CH₃ 16 2,4-Cl₂-phenylC(O)NH—(S—CH)(cyclo- (E)-4-F-benzylidene hexyl)-CH₃ 17 2,4-Cl₂-phenylC(O)NH—(R—CH)(cyclo- (E)-4-F-benzylidene hexyl)-CH₃ 18 2,4-Cl₂-phenylC(O)NH-hexahydro- (E)-4-F-benzylidene cyclopenta[c]pyrrol-2-yl 192,4-Cl₂-phenyl C(O)NH-piperidin-1-yl (E)-4-F-benzylidene

Compounds of Formula (I) and pharmaceutically acceptable forms thereofinclude those selected from:

DEFINITIONS

As used herein, the following terms have the following meanings:

The term “alkyl” means a saturated branched or straight chain monovalenthydrocarbon radical of up to 10 carbon atoms. Alkyl typically includes,but is not limited to, methyl, ethyl, propyl, isopropyl, n-butyl,t-butyl, pentyl, hexyl, heptyl and the like.

The term “lower alkyl” means an alkyl radical of up to 4 carbon atoms.The point of attachment may be on any alkyl or lower alkyl carbon atomand, when further substituted, substituent variables may be placed onany carbon atom.

The term “alkylene” means a saturated branched or straight chainmonovalent hydrocarbon linking group of up to 10 carbon atoms, wherebythe linking group is derived by the removal of one hydrogen atom eachfrom two carbon atoms. Alkylene typically includes, but is not limitedto, methylene, ethylene, propylene, isopropylene, n-butylene,t-butylene, pentylene, hexylene, heptylene and the like. The term “loweralkylene” means an alkylene linking group of up to 4 carbon atoms. Thepoint of attachment may be on any alkylene or lower alkylene carbon atomand, when further substituted, substituent variables may be placed onany carbon atom.

The term “alkylidene” means an alkylene linking group of from 1 to 10carbon atoms having at least one double bond formed between two adjacentcarbon atoms, wherein the double bond is derived by the removal of onehydrogen atom each from the two carbon atoms. Atoms may be orientedabout the double bond in either the cis (E) or trans (Z) conformation.Alkylidene typically includes, but is not limited to, methylidene,vinylidene, propylidene, iso-propylidene, methallylene, allylidene(2-propenylidene), crotylene (2-butenylene), prenylene(3-methyl-2-butenylene) and the like. The term “lower alkylidene” meansa radical or linking group of from 1 to 4 carbon atoms. The point ofattachment may be on any alkylidene or lower alkylidene carbon atom and,when further substituted, substituent variables may be placed on anycarbon atom.

The term “alkoxy” means an alkyl, alkylene or alkylidene radical of upto 10 carbon atoms attached via an oxygen atom, whereby the point ofattachment is formed by the removal of the hydrogen atom from ahydroxide substituent on a parent radical. The term “lower alkoxy” meansan alkyl, alkylene or alkylidene radical of up to 4 carbon atoms. Loweralkoxy typically includes, but is not limited to, methoxy, ethoxy,propoxy, butoxy and the like. When further substituted, substituentvariables may be placed on any alkoxy carbon atom.

The term “cycloalkyl” means a saturated or partially unsaturatedmonocyclic, polycyclic or bridged hydrocarbon ring system radical orlinking group. A ring of 3 to 20 carbon atoms may be designated by C₃₋₂₀cycloalkyl; a ring of 3 to 12 carbon atoms may be designated by C₃₋₁₂cycloalkyl, a ring of 3 to 8 carbon atoms may be designated by C₃₋₈cycloalkyl and the like.

Cycloalkyl typically includes, but is not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl,cyclooctyl, indanyl, indenyl, 1,2,3,4-tetrahydro-naphthalenyl,5,6,7,8-tetrahydro-naphthalenyl,6,7,8,9-tetrahydro-5H-benzocycloheptenyl,5,6,7,8,9,10-hexahydro-benzocyclooctenyl, fluorenyl,bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl,bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl,bicyclo[3.2.1]octenyl, adamantanyl, octahydro-4,7-methano-1H-indenyl,octahydro-2,5-methano-pentalenyl (also referred to ashexahydro-2,5-methano-pentalenyl) and the like. When furthersubstituted, substituent variables may be placed on any ring carbonatom.

The term “heterocyclyl” means a saturated, partially unsaturated orunsaturated monocyclic, polycyclic or bridged hydrocarbon ring systemradical or linking group, wherein at least one ring carbon atom has beenreplaced with one or more heteroatoms independently selected from N, Oor S. A heterocyclyl ring system further includes a ring system havingup to 4 nitrogen atom ring members or a ring system having from 0 to 3nitrogen atom ring members and 1 oxygen or sulfur atom ring member. Whenallowed by available valences, up to two adjacent ring members may be aheteroatom, wherein one heteroatom is nitrogen and the other is selectedfrom N, O or S. A heterocyclyl radical is derived by the removal of onehydrogen atom from a single carbon or nitrogen ring atom. A heterocyclyllinking group is derived by the removal of two hydrogen atoms each fromeither carbon or nitrogen ring atoms.

Heterocyclyl typically includes, but is not limited to, furyl, thienyl,2H-pyrrole, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, pyrrolyl,1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2-imidazolinyl (alsoreferred to as 4,5-dihydro-1H-imidazolyl), imidazolidinyl,2-pyrazolinyl, pyrazolidinyl, pyrazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, triazolyl, thiadiazolyl, tetrazolyl, 2H-pyran, 4H-pyran,pyridinyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl,thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl,azepanyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl,benzo[b]furyl, benzo[b]thienyl, 1H-indazolyl, benzimidazolyl,benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl,cinnolinyl, phthalzinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl,pteridinyl, quinuclidinyl, hexahydro-1,4-diazepinyl, 1,3-benzodioxolyl(also known as 1,3-methylenedioxyphenyl), 2,3-dihydro-1,4-benzodioxinyl(also known as 1,4-ethylenedioxyphenyl), benzo-dihydro-furyl,benzo-tetrahydro-pyranyl, benzo-dihydro-thienyl,5,6,7,8-tetrahydro-4H-cyclohepta(b)thienyl,5,6,7-trihydro-4H-cyclohexa(b)thienyl,5,6-dihydro-4H-cyclopenta(b)thienyl, 2-aza-bicyclo[2.2.1]heptyl,1-aza-bicyclo[2.2.2]octyl, 8-aza-bicyclo[3.2.1]octyl,7-oxa-bicyclo[2.2.1]heptyl and the like.

The term “aryl” means an unsaturated, conjugated 7E electron monocyclicor polycyclic hydrocarbon ring system radical or linking group of 6, 9,10 or 14 carbon atoms. An aryl radical is derived by the removal of onehydrogen atom from a single carbon ring atom. An arylene linking groupis derived by the removal of two hydrogen atoms each of two carbon ringatoms. Aryl typically includes, but is not limited to, phenyl,naphthalenyl, azulenyl, anthracenyl and the like.

The term “amino” means a radical of the formula or —NH₂.

The term “aminoalkyl” means a radical of the formula —NH-alkyl or—N(alkyl)₂.

The term “aminosulfonyl” means a radical of the formula or —SO₂NH₂.

The term “arylalkoxy” means a radical of the formula —O-alkyl-aryl.

The term “aryloxy” means a radical of the formula —O-aryl.

The term “carbamoyl” means a radical of the formula or —C(O)NH₂.

The term “carbamoylalkyl” means a radical of the formula —C(O)NH-alkylor —C(O)N(alkyl)₂.

The term “carbonylalkoxy” means a radical of the formula —C(O)O-alkyl.

The term “carboxy” means a radical of the formula —COOH or —CO₂H.

The term “halo” or “halogen” means fluoro, chloro, bromo or iodo.

The term “lower alkyl-amino” means a radical of the formula —NH-alkyl or—N(alkyl)₂.

The term “lower alkyl-aminosulfonyl” means a radical of the formula—SO₂NH-alkyl or —SO₂N(alkyl)₂.

The term “lower alkyl-sulfonyl” means a radical of the formula—SO₂-alkyl or —C(O)N(alkyl)₂.

The term “substituted” means one or more hydrogen atoms on a coremolecule have been replaced with one or more radicals or linking groups,wherein the linking group, by definition is also further substituted.The ability of a particular radical or linking group to replace ahydrogen atom is optimally expected by one skilled to art to result in achemically stable core molecule.

The term “dependently selected” means one or more substituent variablesare present in a specified combination (e.g. groups of substituentscommonly appearing in a tabular list).

The substituent nomenclature used in the disclosure of the presentinvention was derived using nomenclature rules well known to thoseskilled in the art (e.g., IUPAC).

Pharmaceutical Forms

The compounds of the present invention may be present in the form ofpharmaceutically acceptable salts. For use in medicines, the“pharmaceutically acceptable salts” of the compounds of this inventionrefer to non-toxic acidic/anionic or basic/cationic salt forms.

Suitable pharmaceutically acceptable salts of the compounds of thisinvention include acid addition salts which may, for example, be formedby mixing a solution of the compound according to the invention with asolution of a pharmaceutically acceptable acid such as hydrochloricacid, sulfuric acid, fumaric acid, maleic acid, succinic acid, aceticacid, benzoic acid, citric acid, tartaric acid, carbonic acid orphosphoric acid.

Furthermore when the compounds of the present invention carry an acidicmoiety, suitable pharmaceutically acceptable salts thereof may includealkali metal salts, e.g. sodium or potassium salts; alkaline earth metalsalts, e.g. calcium or magnesium salts; and salts formed with suitableorganic ligands, e.g. quaternary ammonium salts. Thus, representativepharmaceutically acceptable salts include the following: acetate,benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, calcium, camsylate (or camphosulfonate), carbonate, chloride,clavulanate, citrate, dihydrochloride, edetate, fumarate, gluconate,glutamate, hydrabamine, hydrobromine, hydrochloride, iodide,isothionate, lactate, malate, maleate, mandelate, mesylate, nitrate,oleate, pamoate, palmitate, phosphate/diphosphate, salicylate, stearate,sulfate, succinate, tartrate, tosylate.

The present invention includes within its scope prodrugs and metabolitesof the compounds of this invention. In general, such prodrugs andmetabolites will be functional derivatives of the compounds that arereadily convertible in vivo into an active compound.

Thus, in the methods of treatment of the present invention, the term“administering” shall encompass the means for treating, ameliorating orpreventing a syndrome, disorder or disease described herein with acompound specifically disclosed or a compound, or prodrug or metabolitethereof, which would obviously be included within the scope of theinvention albeit not specifically disclosed for certain of the instantcompounds.

The term “prodrug” means a pharmaceutically acceptable form of afunctional derivative of a compound of the invention (or a saltthereof), wherein the prodrug may be: 1) a relatively active precursorwhich converts in vivo to an active prodrug component; 2) a relativelyinactive precursor which converts in vivo to an active prodrugcomponent; or 3) a relatively less active component of the compound thatcontributes to therapeutic biological activity after becoming availablein vivo (i.e., as a metabolite). Conventional procedures for theselection and preparation of suitable prodrug derivatives are describedin, for example, “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

The term “metabolite” means a pharmaceutically acceptable form of ametabolic derivative of a compound of the invention (or a salt thereof),wherein the derivative is a relatively less active component of thecompound that contributes to therapeutic biological activity afterbecoming available in vivo.

The present invention contemplates compounds of various isomers andmixtures thereof. The term “isomer” refers to compounds that have thesame composition and molecular weight but differ in physical and/orchemical properties. Such substances have the same number and kind ofatoms but differ in structure. The structural difference may be inconstitution (geometric isomers) or in an ability to rotate the plane ofpolarized light (stereoisomers).

The term “stereoisomer” refers to isomers of identical constitution thatdiffer in the arrangement of their atoms in space. Enantiomers anddiastereomers are stereoisomers wherein an asymmetrically substitutedcarbon atom acts as a chiral center. The term “chiral” refers to amolecule that is not superposable on its mirror image, implying theabsence of an axis and a plane or center of symmetry. The term“enantiomer” refers to one of a pair of molecular species that aremirror images of each other and are not superposable. The term“diastereomer” refers to stereoisomers that are not related as mirrorimages. The symbols “R” and “S” represent the configuration ofsubstituents around a chiral carbon atom(s). The symbols “R*” and “S*”denote the relative configurations of substituents around a chiralcarbon atom(s).

The term “racemate” or “racemic mixture” refers to a compound ofequimolar quantities of two enantiomeric species, wherein the compoundis devoid of optical activity. The term “optical activity” refers to thedegree to which a chiral molecule or nonracemic mixture of chiralmolecules rotates the plane of polarized light.

The term “geometric isomer” refers to isomers that differ in theorientation of substituent atoms in relationship to a carbon-carbondouble bond, to a cycloalkyl ring or to a bridged bicyclic system.Substituent atoms (other than H) on each side of a carbon-carbon doublebond may be in an E or Z configuration. In the “E” (opposite sided) or“chair” configuration, the substituents are on opposite sides inrelationship to the carbon-carbon double bond; in the “Z” (same sided)or “boat” configuration, the substituents are oriented on the same sidein relationship to the carbon-carbon double bond. Substituent atoms(other than H) attached to a carbocyclic ring may be in a cis or transconfiguration. In the “cis” configuration, the substituents are on thesame side in relationship to the plane of the ring; in the “trans”configuration, the substituents are on opposite sides in relationship tothe plane of the ring. Compounds having a mixture of “cis” and “trans”species are designated “cis/trans”. Substituent atoms (other than H)attached to a bridged bicyclic system may be in an “endo” or “exo”configuration. In the “endo” configuration, the substituents attached toa bridge (not a bridgehead) point toward the larger of the two remainingbridges; in the “exo” configuration, the substituents attached to abridge point toward the smaller of the two remaining bridges.

It is to be understood that the various substituent stereoisomers,geometric isomers and mixtures thereof used to prepare compounds of thepresent invention are either commercially available, can be preparedsynthetically from commercially available starting materials or can beprepared as isomeric mixtures and then obtained as resolved isomersusing techniques well-known to those of ordinary skill in the art.

The isomeric descriptors “R,” “S,” “S*,” “R*,” “E,” “Z,” “cis,” “trans,”“exo” and “endo” are used as described herein for indicating atomconfiguration(s) relative to a core molecule and are intended to be usedas defined in the literature (IUPAC Recommendations for FundamentalStereochemistry (Section E), Pure Appl. Chem., 1976, 45:13-30).

The compounds of the present invention may be prepared as individualisomers by either isomer-specific synthesis or resolved from an isomericmixture. Conventional resolution techniques include forming the freebase of each isomer of an isomeric pair using an optically active salt(followed by fractional crystallization and regeneration of the freebase), forming an ester or amide of each of the isomers of an isomericpair (followed by chromatographic separation and removal of the chiralauxiliary) or resolving an isomeric mixture of either a startingmaterial or a final product using preparative TLC (thin layerchromatography) or a chiral HPLC column.

Furthermore, compounds of the present invention may have one or morepolymorph or amorphous crystalline forms and as such are intended to beincluded in the scope of the invention. In addition, some of thecompounds may form solvates with water (i.e., hydrates) or commonorganic solvents, and such are also intended to be encompassed withinthe scope of this invention.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown in the art.

Therapeutic Use

CB1 and CB2 cannabinoid receptors belong to the G-protein-coupledreceptor (GCPR) family, a receptor super-family with a distinctivepattern of seven transmembrane domains, which inhibits N-type calciumchannels and/or adenylate cyclase to inhibit Q-type calcium channels.CB1 receptors are present in the CNS, predominately expressed in brainregions associated with memory and movement such as the hippocampus(memory storage), cerebellum (coordination of motor function, postureand balance), basal ganglia (movement control), hypothalamus (thermalregulation, neuroendocrine release, appetite), spinal cord(nociception), cerebral cortex (emesis) and periphery regions such aslymphoid organs (cell mediated and innate immunity), vascular smoothmuscle cells (blood pressure), gastrointestinal tract (innateantiinflammatory in the tract and in the esophagus, duodenum, jejunum,ileum and colon, controlling esophageal and gastrointestinal motility),lung smooth muscle cells (bronchodilation), eye ciliary body(intraocular pressure).

CB2 receptors appear to be primarily expressed peripherally in lymphoidtissue (cell mediated and innate immunity), peripheral nerve terminals(peripheral nervous system), spleen immune cells (immune systemmodulation) and retina (intraocular pressure). CB2 mRNA is found in theCNS in cerebellar granule cells (coordinating motor function).Pharmacological and physiological evidence also suggests that there maybe other cannabinoid receptor subtypes that have yet to be cloned andcharacterized.

Where activation or inhibition of a CB receptor appears to mediatevarious syndromes, disorders or diseases, potential areas of clinicalapplication include, but are not limited to, controlling appetite,regulating metabolism, diabetes, reducing glaucoma-associatedintraocular pressure, treating social and mood disorders, treatingseizure-related disorders, treating substance abuse disorders, enhancinglearning, cognition and memory, controlling organ contraction and musclespasm, treating bowel disorders, treating respiratory disorders,treating locomotor activity or movement disorders, treating immune andinflammation disorders, regulating cell growth, use in pain management,use as a neuroprotective agent and the like.

Thus, cannabinoid receptor modulators, including the compounds of theformula (I) or (Ia) of the present invention, are useful for treating,ameliorating or preventing a cannabinoid receptor mediated syndrome,disorder or disease including, but not limited to, controlling appetite,regulating metabolism, diabetes, glaucoma-associated intraocularpressure, pain, social and mood disorders, seizure-related disorders,substance abuse disorders, learning, cognition and/or memory disorders,bowel disorders, respiratory disorders, locomotor activity disorders,movement disorders, immune disorders or inflammation disorders,controlling organ contraction and muscle spasm, enhancing learning,cognition and/or memory, regulating cell growth, providingneuroprotection and the like.

The present invention is directed to a method for treating, amelioratingor preventing a cannabinoid receptor mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a compound offormula (I).

The present invention is directed to a method for treating, amelioratingor preventing a cannabinoid receptor mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a compound offormulae (Ia) or prodrug, metabolite, or composition thereof.

The present invention is directed to a method for treating, amelioratingor preventing a cannabinoid receptor mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject a combination product and/or therapycomprising an effective amount of a compound of formula (I) and atherapeutic agent.

The present invention is directed to a method for treating, amelioratingor preventing a cannabinoid receptor mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject a combination product and/or therapycomprising an effective amount of a compound of formulae (Ia) and atherapeutic agent.

Therapeutic agents contemplated for use in a combination product and/ortherapies of the present invention include an anticonvulsant or acontraceptive agent. The anticonvulsant agents include, and are notlimited to, topiramate, analogs of topiramate, carbamazepine, valproicacid, lamotrigine, gabapentin, phenyloin and the like and mixtures orpharmaceutically acceptable salts thereof. The contraceptive agentsinclude, and are not limited to, such as progestin-only contraceptivesand contraceptives that include both a progestin component and anestrogen component. The invention further includes a pharmaceuticalcomposition wherein the contraceptive is an oral contraceptive, andwherein the contraceptive optionally includes a folic acid component.

The invention also includes a method of contraception in a subjectcomprising the step of administering to the subject a composition,wherein the composition comprises a contraceptive and a CB1 receptorinverse-agonist or antagonist compound of formulae (I) or (Ia), whereinthe composition reduces the urge to smoke in the subject and/or assiststhe subject in losing weight.

The present invention includes cannabinoid receptor modulators usefulfor treating, ameliorating or preventing a CB receptor mediatedsyndrome, disorder or disease. The usefulness of a compound of thepresent invention or composition thereof as a CB modulator can bedetermined according to the methods disclosed herein. The scope of suchuse includes treating, ameliorating or preventing a plurality of CBreceptor mediated syndromes, disorders or diseases.

The present invention is also directed to a method for treating,ameliorating or preventing a CB receptor mediated syndrome, disorder ordisease in a subject in need thereof wherein the syndrome, disorder ordisease is related to appetite, metabolism, diabetes,glaucoma-associated intraocular pressure, social and mood disorders,seizures, substance abuse, learning, cognition or memory, organcontraction or muscle spasm, bowel disorders, respiratory disorders,locomotor activity or movement disorders, immune and inflammationdisorders, unregulated cell growth, pain management, neuroprotection andthe like.

A compound of formulae (I) or (Ia) for use as a CB receptor modulatorincludes a compound having a mean inhibition constant (IC₅₀) for CBreceptor binding activity of between about 50 μM to about 0.01 nM;between about 25 μM to about 0.01 nM; between about 15 μM to about 0.01nM; between about 10 μM to about 0.01 nM; between about 1 μM to about0.01 nM; between about 800 nM to about 0.01 nM; between about 200 nM toabout 0.01 nM; between about 100 nM to about 0.01 nM; between about 80nM to about 0.01 nM; between about 20 nM to about 0.01 nM; between about10 nM to about 0.1 nM; or about 0.1 nM.

A compound of formulae (I) or (Ia) for use as a CB receptor modulator ofthe invention includes a compound having a CB1 agonist IC₅₀ for CB1agonist binding activity of between about 50 μM to about 0.01 nM;between about 25 μM to about 0.01 nM; between about 15 μM to about 0.01nM; between about 10 μM to about 0.01 nM; between about 1 μM to about0.01 nM; between about 800 nM to about 0.01 nM; between about 200 nM toabout 0.01 nM; between about 100 nM to about 0.01 nM; between about 80nM to about 0.01 nM; between about 20 nM to about 0.01 nM; between about10 nM to about 0.1 nM; or about 0.1 nM.

A compound of formulae (I) or (Ia) for use as a CB receptor modulator ofthe invention includes a compound having a CB1 antagonist IC₅₀ for CB1antagonist binding activity of between about 50 μM to about 0.01 nM;between about 25 μM to about 0.01 nM; between about 15 μM to about 0.01nM; between about 10 μM to about 0.01 nM; between about 1 μM to about0.01 nM; between about 800 nM to about 0.01 nM; between about 200 nM toabout 0.01 nM; between about 100 nM to about 0.01 nM; between about 80nM to about 0.01 nM; between about 20 nM to about 0.01 nM; between about10 nM to about 0.1 nM; or about 0.1 nM.

A compound of formulae (I) or (Ia) for use as a CB receptor modulator ofthe invention includes a compound having a CB1 inverse-agonist IC₅₀ forCB1 inverse-agonist binding activity of between about 50 μM to about0.01 nM; between about 25 μM to about 0.01 nM; between about 15 μM toabout 0.01 nM; between about 10 μM to about 0.01 nM; between about 1 μMto about 0.01 nM; between about 800 nM to about 0.01 nM; between about200 nM to about 0.01 nM; between about 100 nM to about 0.01 nM; betweenabout 80 nM to about 0.01 nM; between about 20 nM to about 0.01 nM;between about 10 nM to about 0.1 nM; or about 0.1 nM.

A compound of formulae (I) or (Ia) for use as a CB receptor modulator ofthe invention includes a compound having a CB2 agonist IC₅₀ for CB2agonist binding activity of between about 50 μM to about 0.01 nM;between about 25 μM to about 0.01 nM; between about 15 μM to about 0.01nM; between about 10 μM to about 0.01 nM; between about 1 μM to about0.01 nM; between about 800 nM to about 0.01 nM; between about 200 nM toabout 0.01 nM; between about 100 nM to about 0.01 nM; between about 80nM to about 0.01 nM; between about 20 nM to about 0.01 nM; between about10 nM to about 0.1 nM; or about 0.1 nM.

A compound of formulae (I) or (Ia) for use as a CB receptor modulator ofthe invention includes a compound having a CB2 antagonist IC₅₀ for CB2antagonist binding activity of between about 50 μM to about 0.01 nM;between about 25 μM to about 0.01 nM; between about 15 μM to about 0.01nM; between about 10 μM to about 0.01 nM; between about 1 μM to about0.01 nM; between about 800 nM to about 0.01 nM; between about 200 nM toabout 0.01 nM; between about 100 nM to about 0.01 nM; between about 80nM to about 0.01 nM; between about 20 nM to about 0.01 nM; between about10 nM to about 0.1 nM; or about 0.1 nM.

A compound of formulae (I) or (Ia) for use as a CB receptor modulator ofthe invention includes a compound having a CB2 inverse-agonist IC₅₀ forCB2 inverse-agonist binding activity of between about 50 μM to about0.01 nM; between about 25 μM to about 0.01 nM; between about 15 μM toabout 0.01 nM; between about 10 μM to about 0.01 nM; between about 1 μMto about 0.01 nM; between about 800 nM to about 0.01 nM; between about200 nM to about 0.01 nM; between about 100 nM to about 0.01 nM; betweenabout 80 nM to about 0.01 nM; between about 20 nM to about 0.01 nM;between about 10 nM to about 0.1 nM; or about 0.1 nM.

The term “cannabinoid receptor” refers to any one of the known orheretofore unknown subtypes of the class of cannabinoid receptors thatmay be bound by a cannabinoid modulator compound of the presentinvention; in particular, a cannabinoid receptor selected from the groupconsisting of a CB1 receptor and a CB2 receptor. The term “modulator”further refers to the use of a compound of the invention as a CBreceptor agonist, antagonist or inverse-agonist.

The present invention includes a method for treating, ameliorating orpreventing a CB receptor mediated syndrome, disorder or disease in asubject in need thereof comprising the step of administering to thesubject an effective amount of a compound of the present invention orcomposition thereof, wherein the cannabinoid receptor is a CB1 or CB2receptor; and, the compound is an agonist, antagonist or inverse-agonistof the receptor.

The present invention includes a method for treating, ameliorating orpreventing a CB receptor mediated syndrome, disorder or disease in asubject in need thereof comprising the step of administering to thesubject an effective amount of a compound of the present invention in acombination product and/or therapy with a therapeutic agent such as ananticonvulsant or contraceptive agent or composition thereof, whereinthe cannabinoid receptor is a CB1 or CB2 receptor; and, the compound isan agonist, antagonist or inverse-agonist of the receptor.

It should be understood that contraceptive agents suitable for use in acombination product and/or therapy are not limited to oralcontraceptives, but also include other commonly available contraceptivessuch as those that are administered transdermally, by injection or viaimplant.

Except as further specified, “combination product and/or therapy” meansa pharmaceutical composition comprising a compound of formulae (I) or(Ia) in combination with one or more therapeutic agents. The dosages ofthe compound of formula (I) or (Ia) and the one or more therapeuticagents are adjusted when combined to achieve an effective amount.

The term “subject” as used herein, refers to a patient, which may be ananimal, preferably a mammal, most preferably a human, which has been theobject of treatment, observation or experiment and is at risk of (orsusceptible to) developing a CB receptor mediated syndrome, disorder ordisease.

The term “administering” is to be interpreted in accordance with themethods of the present invention. Such methods include therapeuticallyor prophylactically administering an effective amount of a compositionor medicament of the present invention at different times during thecourse of a therapy or concurrently as a product in a combination form.

Prophylactic administration can occur prior to the manifestation ofsymptoms characteristic of a CB receptor mediated syndrome, disorder ordisease such that the syndrome, disorder or disease is treated,ameliorated, prevented or otherwise delayed in its progression. Themethods of the present invention are further to be understood asembracing all therapeutic or prophylactic treatment regimens used bythose skilled in the art.

The term “effective amount” refers to that amount of active compound orpharmaceutical agent that elicits the biological or medicinal responsein a tissue system, animal or human, that is being sought by aresearcher, veterinarian, medical doctor, or other clinician, whichincludes alleviation of the symptoms of the syndrome, disorder ordisease being treated. The effective amount of a compound of theinvention is from about 0.001 mg/kg/day to about 300 mg/kg/day.

Wherein the present invention is directed to the administration of acombination of a compound of formula (I) and an anticonvulsant orcontraceptive agent, the term “effective amount” means that amount ofthe combination of agents taken together so that the combined effectelicits the desired biological or medicinal response.

As those skilled in the art will appreciate, the effective amounts ofthe components comprising the combination product may be independentlyoptimized and combined to achieve a synergistic result whereby thepathology is reduced more than it would be if the components of thecombination product were used alone.

For example, the effective amount of a combination product and/ortherapy comprising administration of a compound of formula (I) andtopiramate would be the amount of the compound of formula (I) and theamount of topiramate that when taken together or sequentially have acombined effect that is effective. Further, it will be recognized by oneskilled in the art that in the case of combination product and/ortherapy with an effective amount, as in the example above, the amount ofthe compound of formula (I) and/or the amount of the anticonvulsant(e.g., topiramate) individually may or may not be effective.

Wherein the present invention is directed to the administration of acombination product and/or therapy, the instant compound and theanticonvulsant or contraceptive agent may be co-administered by anysuitable means, simultaneously, sequentially or in a singlepharmaceutical composition. Where the instant compound(s) and theanticonvulsant or contraceptive agent components are administeredseparately, the number of dosages of each compound(s) given per day, maynot necessarily be the same, e.g. where one compound may have a greaterduration of activity, and will therefore, be administered lessfrequently.

The compound(s) of formula (I) and the anticonvulsant(s) orcontraceptive agent(s) may be administered via the same or differentroutes of administration. The compound(s) of formula (I) and theanticonvulsant(s) or contraceptive agent(s) may be administered via thesame or different routes of administration.

Suitable examples of methods of administration are orally, intravenous(iv), intramuscular (im), and subcutaneous (sc). Compounds may also beadministrated directly to the nervous system including, but not limitedto the intracerebral, intraventricular, intracerebroventricular,intrathecal, intracisternal, intraspinal and/or peri-spinal routes ofadministration by delivery via intracranial or intravertebral needlesand/or catheters with or without pump devices.

The compound(s) of formula (I) and the anticonvulsant(s) orcontraceptive agent(s) may be administered according to simultaneous oralternating regimens, at the same or different times during the courseof the therapy, concurrently in divided or single forms.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound used, themode of administration, and the strength of the preparation and theadvancement of the disease condition. In addition, factors associatedwith the particular patient being treated, including patient's sex, age,weight, diet, time of administration and concomitant diseases, willresult in the need to adjust dosages.

The term “CB receptor mediated syndrome, disorder, or disease” refers tosyndromes, disorders or diseases associated with a biological responsemediated by a CB receptor such that there is discomfort or decreasedlife expectancy to the organism.

CB receptor mediated syndromes, disorders or diseases can occur in bothanimals and humans and include appetite, metabolism, diabetes, obesity,glaucoma-associated intraocular pressure, social, mood, seizure,substance abuse, learning, cognition, memory, organ contraction, musclespasm, bowel, respiratory, locomotor activity, movement, immune,inflammation, cell growth, pain or neurodegenerative related syndromes,disorders or diseases.

Appetite related syndromes, disorders or diseases include obesity,overweight condition, anorexia, bulimia, cachexia, dysregulated appetiteand the like.

Obesity related syndromes, disorders or diseases include obesity as aresult of genetics, diet, food intake volume, metabolic syndrome,disorder or disease, hypothalmic disorder or disease, age, reducedactivity, abnormal adipose mass distribution, abnormal adiposecompartment distribution and the like.

Metabolism related syndromes, disorders or diseases include metabolicsyndrome, dyslipidemia, elevated blood pressure, diabetes, insulinsensitivity or resistance, hyperinsulinemia, hypercholesterolemia,hyperlipidemias, hypertriglyceridemias, atherosclerosis, hepatomegaly,steatosis, abnormal alanine aminotransferase levels, inflammation,atherosclerosis and the like.

Diabetes related syndromes, disorders or diseases include glucosedysregulation, insulin resistance, glucose intolerance,hyperinsulinemia, dyslipidemia, hypertension, obesity and the like.

Type II diabetes mellitus (non-insulin-dependent diabetes mellitus) is ametabolic disorder (i.e., a metabolism related syndrome, disorder ordisease) in which glucose dysregulation and insulin resistance resultsin chronic, long-term medical complications for both adolescents andadults affecting the eyes, kidneys, nerves and blood vessels and canlead to blindness, end-stage renal disease, myocardial infarction orlimb amputation and the like. Glucose dysregulation includes theinability to make sufficient insulin (abnormal insulin secretion) andthe inability to effectively use insulin (resistance to insulin actionin target organs and tissues). Individuals suffering from Type IIdiabetes mellitus have a relative insulin deficiency. That is, in suchindividuals, plasma insulin levels are normal to high in absolute terms,although they are lower than predicted for the level of plasma glucosethat is present.

Type II diabetes mellitus is characterized by the following clinicalsigns or symptoms: persistently elevated plasma glucose concentration orhyperglycemia; polyuria; polydipsia and/or polyphagia; chronicmicrovascular complications such as retinopathy, nephropathy andneuropathy; and macrovascular complications such as hyperlipidemia andhypertension. These micro- and macro-vascular complications can lead toblindness, end-stage renal disease, limb amputation and myocardialinfarction.

Insulin Resistance Syndrome (IRS) (also referred to as Syndrome X,Metabolic Syndrome or Metabolic Syndrome X) is a disorder that presentsrisk factors for the development of Type II diabetes and cardiovasculardisease including glucose intolerance, hyperinsulinemia, insulinresistance, dyslipidemia (e.g. high triglycerides, low HDL-cholesteroland the like), hypertension and obesity.

Social or mood related syndromes, disorders or diseases includedepression, anxiety, psychosis, social affective disorders or cognitivedisorders and the like.

Substance abuse related syndromes, disorders or diseases include drugabuse, drug withdrawal, alcohol abuse, alcohol withdrawal, nicotinewithdrawal, cocaine abuse, cocaine withdrawal, heroin abuse, heroinwithdrawal and the like.

Learning, cognition or memory related syndromes, disorders or diseasesinclude memory loss or impairment as a result of age, disease, sideeffects of medications (adverse events) and the like.

Muscle spasm syndromes, disorders or diseases include multiplesclerosis, cerebral palsy and the like.

Locomotor activity and movement syndromes, disorders or diseases includestroke, Parkinson's disease, multiple sclerosis, epilepsy and the like.

Bowel related syndromes, disorders or diseases include bowel dysmotilityassociated disorders (either accompanied by pain, diarrhea orconstipation or without), irritable bowel syndrome (and other forms ofbowel dysmotility and the like), inflammatory bowel diseases (such asulcerative colitis, Crohn's disease and the like) and celiac disease.

Respiratory related syndromes, disorders or diseases include chronicpulmonary obstructive disorder, emphysema, asthma, bronchitis and thelike.

Immune or inflammation related syndromes, disorders or diseases includeallergy, rheumatoid arthritis, dermatitis, autoimmune disease,immunodeficiency, chronic neuropathic pain and the like.

Cell growth related syndromes, disorders or diseases includedysregulated mammalian cell proliferation, breast cancer cellproliferation, prostrate cancer cell proliferation and the like.

Pain related syndromes, disorders or diseases include central andperipheral pathway mediated pain, bone and joint pain, migraine headacheassociated pain, cancer pain, menstrual cramps, labor pain and the like.

Neurodegenerative related syndromes, disorders or diseases includeParkinson's Disease, multiple sclerosis, epilepsy, ischemia or secondarybiochemical injury collateral to traumatic head or brain injury, braininflammation, eye injury or stroke and the like.

The present invention includes a method for treating, ameliorating orpreventing a cannabinoid receptor agonist mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a cannabinoidagonist compound of the present invention or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a cannabinoid receptor agonist mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a cannabinoidagonist compound of the present invention in a combination productand/or therapy with an anticonvulsant or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a cannabinoid receptor inverse-agonist mediated syndrome,disorder or disease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a cannabinoidinverse-agonist compound of the present invention or compositionthereof.

The present invention includes a method for treating, ameliorating orpreventing a cannabinoid receptor inverse-agonist mediated syndrome,disorder or disease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a cannabinoidinverse-agonist compound of the present invention in a combinationproduct and/or therapy with an anticonvulsant or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a cannabinoid receptor inverse-agonist mediated syndrome,disorder or disease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a cannabinoidinverse-agonist compound of the present invention in a combinationproduct and/or therapy with one or more contraceptives or compositionthereof.

The present invention includes a method for treating, ameliorating orpreventing a cannabinoid receptor antagonist mediated syndrome, disorderor disease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a cannabinoidantagonist compound of the present invention or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a cannabinoid receptor antagonist mediated syndrome, disorderor disease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a cannabinoidantagonist compound of the present invention in a combination productand/or therapy with an anticonvulsant or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a cannabinoid receptor antagonist mediated syndrome, disorderor disease in a subject in need thereof comprising the step ofadministering to the subject a therapeutically or prophylacticallyeffective amount of a cannabinoid antagonist compound of the presentinvention in a combination product and/or therapy with one or morecontraceptives or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a CB1 receptor agonist mediated syndrome, disorder or diseasein a subject in need thereof comprising the step of administering to thesubject an effective amount of a CB1 agonist compound of the presentinvention or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a CB1 receptor agonist mediated syndrome, disorder or diseasein a subject in need thereof comprising the step of administering to thesubject an effective amount of a CB1 agonist compound of the presentinvention in a combination product and/or therapy with an anticonvulsantor composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a CB1 receptor inverse-agonist mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a CB1inverse-agonist compound of the present invention or compositionthereof.

The present invention includes a method for treating, ameliorating orpreventing a CB1 receptor inverse-agonist mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a CB1inverse-agonist compound of the present invention in a combinationproduct and/or therapy with an anticonvulsant or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a CB1 receptor inverse-agonist mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a CB1inverse-agonist compound of the present invention in a combinationproduct and/or therapy with one or more contraceptives or compositionthereof.

The present invention includes a method for treating, ameliorating orpreventing a CB1 receptor inverse-agonist mediated appetite relatedobesity related or metabolism related syndrome, disorder or disease in asubject in need thereof comprising the step of administering to thesubject an effective amount of a CB1 inverse-agonist compound of thepresent invention or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a CB1 receptor inverse-agonist mediated appetite relatedobesity related or metabolism related syndrome, disorder or disease in asubject in need thereof comprising the step of administering to thesubject an effective amount of a CB1 inverse-agonist compound of thepresent invention in a combination product and/or therapy with ananticonvulsant or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a CB1 receptor inverse-agonist mediated appetite relatedobesity related or metabolism related syndrome, disorder or disease in asubject in need thereof comprising the step of administering to thesubject an effective amount of a CB1 inverse-agonist compound of thepresent invention in a combination product and/or therapy with one ormore contraceptives or composition thereof.

Appetite related syndromes, disorders or diseases include obesity,overweight condition, anorexia, bulimia, cachexia, dysregulated appetiteand the like.

Obesity related syndromes, disorders or diseases include obesity as aresult of genetics, diet, food intake volume, metabolic syndrome,disorder or disease, hypothalmic disorder or disease, age, reducedactivity, abnormal adipose mass distribution, abnormal adiposecompartment distribution and the like.

Metabolism related syndromes, disorders or diseases include metabolicsyndrome, dyslipidemia, elevated blood pressure, diabetes, insulinsensitivity or resistance, hyperinsulinemia, hypercholesterolemia,hyperlipidemias, hypertriglyceridemias, atherosclerosis, hepatomegaly,steatosis, abnormal alanine aminotransferase levels, inflammation,atherosclerosis and the like.

The present invention includes a method for treating, ameliorating orpreventing a CB1 receptor antagonist mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a CB1 antagonistcompound of the present invention or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a CB1 receptor antagonist mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a CB1 antagonistcompound of the present invention in a combination product and/ortherapy with an anticonvulsant or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a CB1 receptor antagonist mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a CB1 antagonistcompound of the present invention in a combination product and/ortherapy with one or more contraceptives or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a CB2 receptor agonist mediated syndrome, disorder or diseasein a subject in need thereof comprising the step of administering to thesubject an effective amount of a CB2 agonist compound of the presentinvention or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a CB2 receptor agonist mediated syndrome, disorder or diseasein a subject in need thereof comprising the step of administering to thesubject an effective amount of a CB2 agonist compound of the presentinvention in a combination product and/or therapy with an anticonvulsantor composition thereof.

The present invention includes include a method for treating,ameliorating or preventing a CB2 receptor inverse-agonist mediatedsyndrome, disorder or disease in a subject in need thereof comprisingthe step of administering to the subject an effective amount of a CB2inverse-agonist compound of the present invention or compositionthereof.

The present invention includes a method for treating, ameliorating orpreventing a CB2 receptor inverse-agonist mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a CB2inverse-agonist compound of the present invention in a combinationproduct and/or therapy with an anticonvulsant or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a CB2 receptor antagonist mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a CB2 antagonistcompound of the present invention or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a CB2 receptor antagonist mediated syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a CB2 antagonistcompound of the present invention in a combination product and/ortherapy with an anticonvulsant or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a metabolism related syndrome, disorder or disease, anappetite related syndrome, disorder or disease, a diabetes relatedsyndrome, disorder or disease, an obesity related syndrome, disorder ordisease or a learning, cognition or memory related syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a compound of thepresent invention or composition thereof.

The present invention includes a method for treating, ameliorating orpreventing a metabolism related syndrome, disorder or disease, anappetite related syndrome, disorder or disease, a diabetes relatedsyndrome, disorder or disease, an obesity related syndrome, disorder ordisease or a learning, cognition or memory related syndrome, disorder ordisease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a compound of thepresent invention in a combination product and/or therapy with ananticonvulsant or composition thereof.

The present invention includes a pharmaceutical composition ormedicament comprising an admixture of a compound of the presentinvention and an optional pharmaceutically acceptable carrier.

The present invention includes a pharmaceutical composition ormedicament comprising an admixture of two or more compounds of thepresent invention and an optional pharmaceutically acceptable carrier.

The present invention also includes a pharmaceutical composition ormedicament comprising an admixture of a compound of formula (I), ananticonvulsant and an optional pharmaceutically acceptable carrier.

Such pharmaceutical compositions are particularly useful for treating asubject suffering from a metabolism related syndrome, disorder ordisease, an appetite related syndrome, disorder or disease, a diabetesrelated syndrome, disorder or disease, an obesity related syndrome,disorder or disease, or a learning, cognition or memory relatedsyndrome, disorder or disease.

Anticonvulsants useful in the methods and compositions of the presentinvention in combination with a compound of formula (I) or (Ia) include,but are not limited to, topiramate, analogs of topiramate,carbamazepine, valproic acid, lamotrigine, gabapentin, phenyloin and thelike and mixtures or pharmaceutically acceptable salts thereof.

Topiramate, 2,3:4,5-bis-O-(1-methylethylidene)-β-D-fructopyranosesulfamate, is currently marketed for the treatment of seizures inpatients with simple and complex partial epilepsy and seizures inpatients with primary or secondary generalized seizures in the UnitedStates, Europe and most other markets throughout the world. Topiramateis currently available for oral administration in round tabletscontaining 25 mg, 100 mg or 200 mg of active agent, and as 15 mg and 25mg sprinkle capsules for oral administration as whole capsules or openedand sprinkled onto soft food. U.S. Pat. No. 4,513,006, incorporatedherein by reference, discloses topiramate and analogs of topiramate,their manufacture and use for treating epilepsy. Additionally,topiramate may also be made by the process disclosed in U.S. Pat. Nos.5,242,942 and 5,384,327, which are incorporated by reference herein. Theterm “analogs of topiramate”, as used herein, refers to the sulfamatecompounds of formula (I), which are disclosed in U.S. Pat. No. 4,513,006(see, e.g., column 1, lines 36-65 of U.S. Pat. No. 4,513,006).

For use in the methods of the present invention in combination with acompound of the formula (I) or (Ia), topiramate (or an analog oftopiramate) can be administered in the range of about 10 to about 1000mg daily, preferably in the range of about 10 to about 650 mg daily,more preferably in the range of about 15 to about 325 mg once or twicedaily.

Carbamazepine, 5H-dibenz[b,f]azepine-5-carboxamide, is an anticonvulsantand specific analgesic for trigeminal neuralgia, available for oraladministration as chewable tablets of 100 mg, tablets of 200 mg, XR(extended release) tablets of 100, 200, and 400 mg, and as a suspensionof 100 mg/5 mL (teaspoon); U.S. Pat. No. 2,948,718, herein incorporatedby reference in its entirety, discloses carbamazepine and its methods ofuse.

For use in the methods of the present invention in combination with acompound of the formula (I) or (Ia), carbamazepine can be administeredin the range of about 200 to about 1200 mg/day; preferably, about 400mg/day.

Valproic acid, 2-propylpentanoic acid or dipropylacetic acid, is anantiepileptic agent commercially available as soft elastic capsulescontaining 250 mg valproic acid, and as syrup containing the equivalentof 250 mg valproic acid per 5 mL as the sodium salt. Valproic acid andvarious pharmaceutically acceptable salts are disclosed in U.S. Pat. No.4,699,927, which is incorporated by reference herein in its entirety.

For use in the methods of the present invention in combination with acompound of the formula (I) or (Ia), valproic acid can be administeredin the range of about 250 to about 2500 mg/day; preferably, about 1000mg/day.

Lamotrigine, 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine, is anantiepileptic drug commercially available for oral administration astablets containing 25 mg, 100 mg, 150 mg, and 200 mg of lamotrigine, andas chewable dispersible tablets containing 2 mg, 5 mg, or 25 mg oflamotrigine. Lamotrigine and its uses are disclosed in U.S. Pat. No.4,486,354, incorporated by reference herein in its entirety.

For use in the methods of the present invention in combination with acompound of the formula (I) or (Ia), lamotrigine can be administered inthe range of about 50 to about 600 mg/day in one to two doses;preferably, about 200 to about 400 mg/day; most preferably, about 200mg/day.

Gabapentin, 1-(aminomethyl)cyclohexaneacetic acid, is commerciallyavailable for the adjunctive treatment of epilepsy and for postherpeticneuralgia in adults as capsules containing 100 mg, 300 mg, and 400 mg ofgabapentin, film-coated tablets containing 600 mg and 800 mg ofgabapentin, and an oral solution containing 250 mg/5 mL of gabapentin.Gabapentin and its methods of use are described in U.S. Pat. Nos.4,024,175 and 4,087,544, herein incorporated by reference in theirentirety.

For use in the methods of the present invention in combination with acompound of the formula (I) or (Ia), gabapentin can be administered inthe range of about 300 to about 3600 mg/day in two to three divideddoses; preferably, about 300 to about 1800 mg/day; most preferably,about 900 mg/day.

Phenyloin sodium, 5,5-diphenylhydantoin sodium salt, is ananticonvulsant, which is commercially available for oral administrationas capsules containing 100 mg, 200 mg or 300 mg of phenyloin sodium.

For use in the methods of the present invention in combination with acompound of the formula (I) or (Ia), phenyloin sodium can beadministered in the range of about 100 to about 500 mg/day; preferably,about 300 to about 400 mg/day; most preferably, about 300 mg/day.

The present invention also includes a pharmaceutical composition ormedicament comprising an admixture of a compound of formula (I) or (Ia),one or more contraceptives and an optional pharmaceutically acceptablecarrier.

Contraceptives suitable for use in a combination product and/or therapyinclude, for example, ORTHO CYCLEN®, ORTHO TRI-CYCLEN®, ORTHO TRI-CYCLENLO®, and ORTHO EVRA®, all available from Ortho-McNeil Pharmaceutical,Inc., Raritan, N.J. It should also be understood that contraceptivessuitable for use in the invention encompass those contraceptives thatinclude a folic acid component.

Smoking and/or obesity have been identified as risk factors in womentaking oral contraceptives. CB1 receptor antagonists and inverseagonists have been found to be useful therapeutic agents for reducingthe urge to smoke and for assisting patients with eating disorders tolose weight.

Accordingly, the invention further includes a method of reducing therisk factors associated with smoking and/or obesity for women takingcontraceptives by co-administering with a contraceptive at least one ofa CB1 receptor antagonist and/or CB1 receptor inverse-agonist compoundof formula (I) or (Ia).

The use of such compounds or a pharmaceutical composition or medicamentthereof is to reduce the desire to smoke and/or to assist in weight lossfor patients taking contraceptives.

Pharmaceutical Compositions

The term “composition” refers to a product comprising the specifiedingredients in the specified amounts, as well as any product thatresults, directly or indirectly, from combinations of the specifiedingredients in the specified amounts. The invention further comprisesmixing one or more of the compounds of the invention and apharmaceutically acceptable carrier; and, includes those compositionsresulting from such a process. Contemplated processes include bothtraditional and modern pharmaceutical techniques.

Pharmaceutical compositions of the invention may, alternatively or inaddition to a compound of formula (I) or (Ia), comprise apharmaceutically acceptable salt of a compound of formula (I) or (Ia) ora prodrug or pharmaceutically active metabolite of such a compound orsalt in admixture with a pharmaceutically acceptable carrier.

The term “medicament” refers to a product for use in treating,ameliorating or preventing a cannabinoid receptor mediated syndrome,disorder or disease.

“Pharmaceutically acceptable carrier” means molecular entities andcompositions that are of sufficient purity and quality for use in theformulation of a composition of the invention and that, whenappropriately administered to an animal or a human, do not produce anadverse, allergic, or other untoward reaction.

Since both clinical and veterinary uses are equally included within thescope of the present invention, a pharmaceutically acceptableformulation would include a composition or medicament formulation foreither clinical or veterinary use.

The present invention includes a process for making the composition ormedicament comprising mixing any of the instant compounds and apharmaceutically acceptable carrier and include those compositions ormedicaments resulting from such a process. Contemplated processesinclude both conventional and unconventional pharmaceutical techniques.Other examples include a composition or medicament comprising a mixtureof at least two of the instant compounds in association with apharmaceutically acceptable carrier.

The composition or medicament may be administered in a wide variety ofdosage unit forms depending on the method of administration; whereinsuch methods include (without limitation) oral, sublingual, nasal(inhaled or insufflated), transdermal, rectal, vaginal, topical (with orwithout occlusion), intravenous (bolus or infusion) or for injection(intraperitoneally, subcutaneously, intramuscularly, intratumorally orparenterally) using a suitable dosage form well known to those ofordinary skill in the area of pharmaceutical administration.Accordingly, the term “dosage unit” or “dosage form” is alternativelyused to refer to (without limitation) a tablet, pill, capsule, solution,syrup, elixir, emulsion, suspension, suppository, powder, granule orsterile solution, emulsion or suspension (for injection from an ampouleor using a device such as an auto-injector or for use as an aerosol,spray or drop). Furthermore, the composition may be provided in a formsuitable for weekly or monthly administration (e.g. as an insoluble saltof the active compound (such as the decanoate salt) adapted to provide adepot preparation for intramuscular injection).

In preparing a dosage form, the principal active ingredient (such as acompound of the present invention or a pharmaceutically acceptable salt,racemate, enantiomer, or diastereomer thereof) is optionally mixed withone or more pharmaceutical carriers (such as a starch, sugar, diluent,granulating agent, lubricant, glidant, binder, disintegrating agent andthe like), one or more inert pharmaceutical excipients (such as water,glycols, oils, alcohols, flavoring agents, preservatives, coloringagents, syrup and the like), one or more conventional tabletingingredient (such as corn starch, lactose, sucrose, sorbitol, talc,stearic acid, magnesium stearate, dicalcium phosphate, any of a varietyof gums and the like) and a diluent (such as water and the like) to forma homogeneous composition (whereby the active ingredient is dispersed orsuspended evenly throughout the mixture) which may be readily subdividedinto dosage units containing equal amounts of a compound of the presentinvention.

Binders include, without limitation, starch, gelatin, natural sugars(such as glucose, beta-lactose and the like), corn sweeteners andnatural and synthetic gums (such as acacia, tragacanth, sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and the like). Disintegrating agents include, withoutlimitation, starch, methyl cellulose, agar, bentonite, xanthan gum andthe like.

Because of the ease of administration, tablets and capsules represent anadvantageous oral dosage unit form, wherein solid pharmaceuticalcarriers are employed. If desired, tablets may be sugar or film coatedor enteric-coated by standard techniques. Tablets may also be coated orotherwise compounded to provide a prolonged therapeutic effect. Forexample, the dosage form may comprise an inner dosage and an outerdosage component, whereby the outer component is in the form of anenvelope over the inner component. The two components may further beseparated by a layer, which resists disintegration in the stomach (suchas an enteric layer) and permits the inner component to pass intact intothe duodenum or a layer which delays or sustains release. A variety ofenteric and nonenteric layer or coating materials may be used (such aspolymeric acids, shellacs, acetyl alcohol, cellulose acetate and thelike) or combinations thereof.

The liquid forms in which a compound of the present invention may beincorporated for oral administration include (without limitation),aqueous solutions, suitably flavored syrups, aqueous or oil suspensions(using a suitable synthetic or natural gum dispersing or suspendingagent such as tragacanth, acacia, alginate, dextran, sodiumcarboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone, gelatinand the like), flavored emulsions (using a suitable edible oil such ascottonseed oil, sesame oil, coconut oil, peanut oil and the like),elixirs and other similar liquid forms with a variety ofpharmaceutically acceptable vehicles.

As is also known in the art, the compounds may alternatively beadministered parenterally via injection. For parenteral administration,sterile solutions or injectable suspensions may be parenteral vehicleswherein appropriate liquid carriers, suspending agents and the like areemployed. Sterile solutions are a preferred parenteral vehicle. Isotonicpreparations that generally contain suitable preservatives are employedwhen intravenous administration is desired. A parenteral formulation mayconsist of the active ingredient dissolved in or mixed with anappropriate inert liquid carrier. Acceptable liquid carriers compriseaqueous solvents and the like and other optional ingredients for aidingsolubility or preservation. Such aqueous solvents include sterile water,Ringer's solution or an isotonic aqueous saline solution. Alternatively,a sterile non-volatile oil may be employed as a solvent agent. Otheroptional ingredients include vegetable oils (such as peanut oil,cottonseed oil, sesame oil and the like), organic solvents (such assolketal, glycerol, formyl and the like), preservatives, isotonizers,solubilizers, stabilizers, pain-soothing agents and the like. Aparenteral formulation is prepared by dissolving or suspending theactive ingredient in the liquid carrier whereby the final dosage unitcontains from 0.005 to 10% by weight of the active ingredient.

Compounds of the present invention may be administered intranasallyusing a suitable intranasal vehicle. Compounds of the present inventionmay be administered topically using a suitable topical transdermalvehicle or a transdermal patch. Administration via a transdermaldelivery system requires a continuous rather than intermittent dosageregimen.

Compounds of the present invention may also be administered via a rapiddissolving or a slow release composition, wherein the compositionincludes a biodegradable rapid dissolving or slow release carrier (suchas a polymer carrier and the like) and a compound of the invention.Rapid dissolving or slow release carriers are well known in the art andare used to form complexes that capture therein an active compound(s)and either rapidly or slowly degrade/dissolve in a suitable environment(e.g., aqueous, acidic, basic, etc). Such particles are useful becausethey degrade/dissolve in body fluids and release the active compound(s)therein. The particle size of a compound of the present invention,carrier or any excipient used in such a composition may be optimallyadjusted using techniques known to those of ordinary skill in the art.

The present invention includes a composition of an instant compound orprodrug thereof present in a prophylactically or therapeuticallyeffective amount necessary for symptomatic relief to a subject in needthereof A prophylactically or therapeutically effective amount of aninstant compound or prodrug thereof may range from about 0.01 ng toabout 1 g and may be constituted into any form suitable for theadministration method and regimen selected for the subject.

Depending on the subject and disease to be treated, the prophylacticallyor therapeutically effective amount for a person of average body weightof about 70 kg per day may range from about 0.01 ng/kg to about 300mg/kg; from about 0.1 ng/kg to about 200 mg/kg; from about 0.5 ng/kg toabout 100 mg/kg; or, from about 0.1 ng/kg to about 50 mg/kg.

An optimal prophylactically or therapeutically effective amount andadministration method and regimen may be readily determined by thoseskilled in the art, and will vary depending on factors associated withthe particular patient being treated (age, weight, diet and time ofadministration), the severity of the condition being treated, thecompound and dosage unit being employed, the mode of administration andthe strength of the preparation.

Dosage unit(s) may be administered to achieve the therapeutically orprophylactically effective amount in a regimen of from about once perday to about 5 times per day. The preferred dosage unit for oraladministration is a tablet containing 0.01, 0.05, 0.1, 0.5, 1.0, 2.5,5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 or 500 mg of the activeingredient.

Representative compounds for use in the therapeutic methods andpharmaceutical compositions described herein include compounds selectedfrom:

Cpd Name 1 1-cyclohexyl-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3-carboxylic acid (1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide, 21-cyclohexyl-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3- carboxylicacid (adamantan-1-ylmethyl)-amide, 31-cyclopentyl-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3- carboxylicacid (adamantan-1-ylmethyl)-amide, 42-[(1-cyclohexyl-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3-carbonyl)-amino]-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester, 51-cyclopentyl-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3- carboxylicacid (1-adamantan-1-yl-ethyl)-amide, 61-cyclohexyl-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3- carboxylicacid (1-adamantan-1-yl-ethyl)-amide, 11(9E)-1-(2,4-dichloro-phenyl)-9-(4-fluoro-benzylidene)-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3-carboxylic acid N′-(2,4-dichloro-phenyl)-hydrazide, 12(9E)-1-(2,4-dichloro-phenyl)-9-(4-fluoro-benzylidene)-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3-carboxylic acid [(1R)-1-phenyl-ethyl]-amide, 13(9E)-1-(2,4-dichloro-phenyl)-9-(4-fluoro-benzylidene)-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3-carboxylic acid [(1R)-1-pyridin-2-yl-ethyl]-amide, 14(9E)-[1-(2,4-dichloro-phenyl)-9-(4-fluoro-benzylidene)-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazol-3-yl]-piperidin-1-yl-methanone, 15(9E)-1-(2,4-dichloro-phenyl)-9-(4-fluoro-benzylidene)-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3-carboxylic acid [(1S)-1-phenyl-ethyl]-amide, 16(9E)-1-(2,4-dichloro-phenyl)-9-(4-fluoro-benzylidene)-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3-carboxylic acid [(1S)-1-cyclohexyl-ethyl]-amide, 17(9E)-1-(2,4-dichloro-phenyl)-9-(4-fluoro-benzylidene)-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3-carboxylic acid [(1R)-1-cyclohexyl-ethyl]-amide, 18(9E)-1-(2,4-dichloro-phenyl)-9-(4-fluoro-benzylidene)-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3-carboxylic acid (hexahydro-cyclopenta[c]pyrrol-2-yl)-amide, or 19(9E)-1-(2,4-dichloro-phenyl)-9-(4-fluoro-benzylidene)-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3-carboxylic acid piperidin-1- ylamide.Synthetic Methods

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic schemes described below and areillustrated more particularly in the specific synthetic examples thatfollow. The general schemes and specific examples are offered by way ofillustration; the invention should not be construed as being limited bythe chemical reactions and conditions expressed. The methods forpreparing the various starting materials used in the schemes andexamples are well within the skill of persons versed in the art. Noattempt has been made to optimize the yields obtained in any of theexample reactions. One skilled in the art would know how to increasesuch yields through routine variations in reaction times, temperatures,solvents and/or reagents.

The terms used in describing the invention are commonly used and knownto those skilled in the art. When used herein, the followingabbreviations and formulae have the indicated meanings:

Abbreviation Meaning Cpd compound EDCI1-(3-dimethylaminopropyl)-3-ethylcarbodiimide DCM dichloromethane DMAP4-dimethylaminopyridine EtOAc ethyl acetate Et₂O anhydrous ether K₂CO₃potassium carbonate LDA lithium diisopropylamine LHMDS or LiHMDS lithiumbis(trimethylsilyl)amide min(s)/hr(s) minute(s)/hour(s) N₂ nitrogenRT/rt/r.t. room temperature SOCl₂ thionyl chloride TEA or Et₃Ntriethylamine THF tetrahydrofuran

A solution of cyclooctanone Compound A1 (in a solvent such as THF andthe like) is reacted with a Compound A2 (in a solvent such as anhydrousTHF and the like, wherein Q-X_(y) represents a suitable reaction groupand wherein certain portions of Q-X_(y) are incorporated into X₄R₄ as aproduct of the reaction) under basic conditions to provide Compound A3.

A solution of Compound A3 (in a solvent such as Et₂O, THF and the likeor a mixture thereof) is added dropwise to a reagent solution (such asLHMDS and the like in a solvent such as Et₂O or THF and the like or amixture thereof) at −78° C. under an inert atmosphere and stirred atabout −78° C. for about 40 mins. A solution of Compound A4 (in a solventsuch as Et₂O and the like) is added dropwise and the mixture is stirredat about −78° C. for about 1 hr, then allowed to warm to r.t. over aperiod of about 2 hrs to yield Compound A5 as a crude product usedwithout further purification in the next step.

A reagent (such as K₂CO₃ and the like) and a substituted hydrazine monoor dihydrochloride Compound A6 are added to a solution of Compound A5(in a solvent such as one or more of MeOH, EtOH, CH₂Cl₂ and the like) ata temperature of about 0° C. under an inert atmosphere. The mixture wasstirred overnight, while warming to r.t., to provide Compound A7 afterworkup.

The X_(a)R_(a) substituent moiety on Compound A6 represents thepossibility that, after isomer separation, the substituted amine groupmay be found either on the N¹ position as X₁R₁ or on the N² position asX₂R₂. Compound A7 represents a mixture of isomers, wherein a mixture ofX₁R₁ and X₂R₂ isomers are present.

The hydrazine hydrochloride or dihydrochloride Compound A6 may beconverted to the free base by methods known to those skilled in the art.In the examples of the present invention, the free base is preparedeither in situ (as shown for illustrative purposes in this Scheme) orseparately (then added to the reaction mixture) by reaction with K₂CO₃.

As illustrated in this Scheme, Compound A6 may also be furthersubstituted with a variety of X_(a)R_(a) substituents (as previouslydefined herein). In many instances, the substituted hydrazine CompoundA6 is commercially available. When not commercially available, aparticularly substituted Compound A6 may be prepared by methods known tothose skilled in the art.

More specifically, a halogenated X_(a)R_(a) substituent moiety isreacted with a hydrazine hydrate solution at reflux and used withoutfurther purification in place of Compound A6.

The Compound A7 isomeric mixture is separated via flash chromatography(eluted with a suitable solvent mixture such as from about 20% to about30% EtOAc and the like in hexane and the like) to provide a purifiedmajor isomer Compound A8 and a minor isomer Compound A9.

The major isomer Compound A8 is substituted on the N¹ position with X₁R₁(X₂R₂ is necessarily absent). The minor isomer Compound A9 issubstituted on the N² position with X₂R₂ (wherein X₁R₁ is absent).

The separated major isomer Compound A8 is treated with a reagentsolution (such as a mixture of NaOH or LiOH in a solvent such as water,MeOH, THF and the like or a mixture thereof) and stirred overnight toprovide Compound A10 after workup.

A reagent solution (such as SOCl₂ and the like in a solvent such asCH₂Cl₂ and the like) is added to Compound A10 at ambient temperatureunder an inert nitrogen atmosphere. The reaction mixture is stirred atreflux temperature for about 15 mins to provide Compound A10 afterworkup.

A solution of Compound A10 (optionally mixed with TEA and the like) isadded to a solution of a substituted amine Compound A12 (in a solventsuch as CH₂Cl₂ and the like) at ambient temperature under an inertnitrogen atmosphere. The mixture is stirred at r.t. for a period of timeto provide Compound A13 after workup.

For purposes of this Scheme, the X_(b) portion of Compound A12 is anoptionally substituted amino moiety, whereby the Compound A13 X₃R₃substituent moiety incorporates the C(O) portion of the C³ substituentof Compound A11 and the X_(b) portion from X_(b)R_(b) of Compound A12.

In general, Compound A12 is a commercially available substituted amineWhen not commercially available, a particularly substituted Compound A12may be prepared by methods known to those skilled in the art amenablefor reaction with a suitably prepared Compound A11.

For example, functional group transformations known to those skilled inthe art may be used to prepare Compound A10 for reaction with aparticularly substituted Compound A12 wherein X_(b)R_(b) is analkylsulfonylamino moiety or an alkylcarbamoyl moiety each furthersubstituted on the amino portion.

The synthetic examples that follow herein describe more completely thepreparation of particular compounds included within the scope of thepresent invention.

Example 11-cyclohexyl-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3-carboxylicacid (1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide (Cpd 1)

A solution of cyclooctanone Compound 1a (25.0 g, 0.20 Mol) in Et₂O (100mL) was added dropwise to a solution of LHMDS (0.33 L, 0.20 Mol) inanhydrous Et₂O (200 mL) at −78° C. under a N₂ atmosphere. The mixturewas maintained at −78° C. and stirred for 60 min. Compound 1b (29.2 g,0.20 Mol) in anhydrous Et₂O (100 mL) was added dropwise and the mixturewas stirred at −78° C. for 1 hr, then allowed to warm to r.t. over 3 hrsand stirred for 1 hr. The reaction mixture was quenched with water (100mL) and diluted with EtOAc (300 mL), then the separated organic layerwas washed with brine, dried with anhydrous sodium sulfate, thenfiltered and concentrated in vacuo. The resulting crude product waspurified by flash chromatography (eluted with 20% EtOAc in hexane) toprovide Compound 1c (36 g, 80%).

Cyclohexyl-hydrazine hydrochloride Compound 1d (2.5 g, 16.7 mMol) andK₂CO₃ (2.31 g, 16.7 mMol) were added to a solution of Compound 1c (3.7g, 16.7 mMol) in EtOH (50 mL) at ambient temperature under a N₂atmosphere. The reaction mixture was stirred overnight, then quenchedwith water (25 mL) and diluted with EtOAc (500 mL). The organic layerwas separated, washed with brine and dried over anhydrous sodiumsulfate, then filtered and concentrated in vacuo to provide Compound 1e(5 g), which was used in the next step without further purification.

1N NaOH (50 mL) was added to Compound 1e (5 g, 16.4 mMol) in THF (25mL). The mixture was stirred for 30 hours, acidified to pH 2 with 1N HCland extracted with EtOAc (100 mL). The organic layer was washed withbrine, dried over sodium sulfate, then filtered and concentrated invacuo to yield Compound 1f as a white solid.

Thionyl chloride (5.87 g, 49.3 mMol) was added to a solution of Compound1f in CH₂Cl₂ (50 mL) at ambient temperature under a N₂ atmosphere. Thereaction was stirred for 3 hrs and concentrated in vacuo to provideCompound 1 g (4.5 g, 91%) as a light brown solid.

A solution of Compound 1g (0.130 g, 0.46 mMol) in DCM (5 mL) was addeddropwise to a solution of 1,3,3-trimethyl-bicyclo[2.2.1]hept-2-ylamineCompound 1h (0.87 g, 0.46 mMol) and Et₃N (0.10 g, 0.98 mMol) in CH₂Cl₂(10 mL) at ambient temperature under a N₂ atmosphere.

The reaction mixture was stirred at r.t. for 3 hrs, then diluted withwater (10 mL) and CH₂Cl₂ (50 mL). The organic layer was separated anddried with anhydrous sodium sulfate, then filtered and concentrated invacuo. The resulting crude oil was purified by flash chromatographyusing 20% EtOAc in hexane to provide Compound 1 (0.115 g, 63%) as awhite solid. MS m/z 412 (M⁺).

Following the procedure of Example 1, substituting the appropriatestarting materials, reagents and solvents, the following compounds wereprepared:

Cpd Name MS 2 1-cyclohexyl-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3-424 carboxylic acid (adamantan-1-ylmethyl)-amide 31-cyclopentyl-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3- 410carboxylic acid (adamantan-1-ylmethyl)-amide 42-[(1-cyclohexyl-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole- 4423-carbonyl)-amino]-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester 51-cyclopentyl-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3- 424carboxylic acid (1-adamantan-1-yl-ethyl)-amide 61-cyclohexyl-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3- 438carboxylic acid (1-adamantan-1-yl-ethyl)-amide 71-cyclopentyl-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3- 398carboxylic acid (1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide 81-cyclobutyl-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3- 384carboxylic acid (1,3,3-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide 91-cyclobutyl-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3- 396carboxylic acid (adamantan-1-ylmethyl)-amide 101-cyclobutyl-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3- 410carboxylic acid (1-adamantan-1-yl-ethyl)-amide

Example 2(9E)-1-(2,4-dichloro-phenyl)-9-(4-fluoro-benzylidene)-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3-carboxylicacid [(1S)-1-phenyl-ethyl]-amide (Cpd 15)

A solution of KOH (0.25 g, 4.46 mMol) in water (4.4 mL), was added to4-fluoro-benzaldehyde Compound 2a (1.07 mL, 10 mMol) and the mixture washeated to 65° C. Cyclooctanone Compound 1a (1.26 g, 10 mMol) was addeddropwise over a period of 15 mins. The mixture was refluxed for 5 hrs,then allowed to stir overnight at room temperature. The reaction mixturewas acidified with 1N HCl (26 mL) and extracted with EtOAc (100 mL). Theorganic layer was washed with brine, dried over Na₂SO₄, then filteredand concentrated. The resulting yellow residue was purified on silicagel column with 3% EtOAc/Hexane to give(2E)-2-(4-fluoro-benzylidene)-cyclooctanone Compound 2b (1.04 g, 44.8%).

A solution of Compound 2b (1.04 g, 4.48 mMol) in THF (5 mL) was addeddropwise to a solution of LHMDS (5.4 mL, 1M solution in THF) at −78° C.The resulting mixture was stirred at −78° C. for 1 hr, then oxalic aciddiethyl ester Compound 1b (0.61 ml, 4.48 mmol) was added dropwise. Themixture was stirred at −78° C. for 1 hr, then allowed to gradually warmup to room temperature and stirred overnight at room temperature. Thereaction mixture was acidified with 1N HCl and extracted with EtOAc (150mL). The organic layer was washed with 1N HCl (1×) and water (2×) anddried over Na₂SO₄, then filtered and concentrated to give(3E)-[3-(4-fluoro-benzylidene)-2-oxo-cyclooctyl]-oxo-acetic acid ethylester Compound 2c as a yellow oil, which was used in the next stepwithout further purification.

K₂CO₃ (0.62 g, 4.48 mmol) and (2,4-dichloro-phenyl)-hydrazinehydrochloride Compound 2d (0.96 g, 4.50 mmol) were added to a solutionof Compound 2c (4.48 mMol) in ethanol (30 mL) and the mixture wasstirred at room temperature overnight. The reaction mixture was filteredand washed with ethanol (20 mL). The filtrate was concentrated andpurified on a silica gel column with 15% EtOAc/Hexane to give(9E)-1-(2,4-dichloro-phenyl)-9-(4-fluoro-benzylidene)-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3-carboxylicacid ethyl ester Compound 2e (0.37 g, 17.5% for last 2 steps).

A solution of LiOH (43 mg, 1.8 mMol) in water (2 mL) was added to asolution of Compound 2e (0.17 g, 0.36 mMol) in a mixture of THF (6 mL)and ethanol (1 mL). The mixture was stirred at room temperatureovernight, then concentrated and acidified with 1N HCl (10 mL). Theaqueous solution was extracted with EtOAc (100 mL). The organic layerwas washed with brine and dried over Na₂SO₄, then filtered andconcentrated to give(9E)-1-(2,4-dichloro-phenyl)-9-(4-fluoro-benzylidene)-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3-carboxylicacid Compound 2f (0.15 g, 93.6%) as a yellow solid.

SOCl₂ (0.3 mL, 4.1 mMol) was added to a solution of Compound 2f (0.15 g,0.34 mMol) in DCM (2 mL). The mixture was refluxed for 3 hrs, thenconcentrated under high vacuum to give(9E)-1-(2,4-dichloro-phenyl)-9-(4-fluoro-benzylidene)-4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3-carbonylchloride Compound 2g (0.15 g, 95.3%) as a yellow solid.

A solution of (1S)-1-phenyl-ethylamine (0.013 g, 0.11 mMol) and TEA(0.03 ml, 0.22 mmol) was added to a solution of Compound 2g (30 mg,0.065 mMol) in DCM (2 ml). The reaction mixture was stirred at roomtemperature for 1 hr, diluted with DCM and washed with 1N HCl. Theorganic layer was washed with water and dried over Na₂SO₄, then filteredand concentrated. The resulting yellow residue was purified on apreparative silica gel plate with 20% EtOAc/Hexane to give Compound 15(30 mg, 84.2%) as a pale yellow powder. MS m/z 548 (M⁺).

Following the procedure of Example 2, substituting the appropriatestarting materials, reagents and solvents, the following compounds wereprepared:

Cpd Name MS 11 (9E)-1-(2,4-dichloro-phenyl)-9-(4-fluoro-benzylidene)-603 4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3-carboxylic acidN′-(2,4-dichloro-phenyl)-hydrazide 12(9E)-1-(2,4-dichloro-phenyl)-9-(4-fluoro-benzylidene)- 5484,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3-carboxylic acid[(1R)-1-phenyl-ethyl]-amide 13(9E)-1-(2,4-dichloro-phenyl)-9-(4-fluoro-benzylidene)- 5494,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3-carboxylic acid[(1R)-1-pyridin-2-yl-ethyl]-amide 14(9E)-[1-(2,4-dichloro-phenyl)-9-(4-fluoro-benzylidene)- 5124,5,6,7,8,9-hexahydro-1H-cyclooctapyrazol-3-yl]-piperidin-1-yl-methanone 16 (9E)-1-(2,4-dichloro-phenyl)-9-(4-fluoro-benzylidene)-554 4,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3-carboxylic acid[(1S)-1-cyclohexyl-ethyl]-amide 17(9E)-1-(2,4-dichloro-phenyl)-9-(4-fluoro-benzylidene)- 5544,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3-carboxylic acid[(1R)-1-cyclohexyl-ethyl]-amide 18(9E)-1-(2,4-dichloro-phenyl)-9-(4-fluoro-benzylidene)- 5534,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3-carboxylic acid(hexahydro-cyclopenta[c]pyrrol-2-yl)-amide 19(9E)-1-(2,4-dichloro-phenyl)-9-(4-fluoro-benzylidene)- 5274,5,6,7,8,9-hexahydro-1H-cyclooctapyrazole-3-carboxylic acidpiperidin-1-ylamide

Additional compounds may be made according to the synthetic methods ofthe present invention by one skilled in the art, differing only inpossible starting materials, reagents and conditions used in the instantmethods.

Biological Examples

The following examples illustrate that the compounds of the presentinvention are CB receptor modulators useful for treating, amelioratingor preventing a cannabinoid receptor mediated syndrome, disorder ordisease in a subject in need thereof.

Example 1 Binding Assay for CB1 or CB2 Agonists or Inverse Agonists

The human CB1 and CB2 receptors were stably expressed in SK-N-MC cellstransfected with pcDNA3 CB-1 (human) or pcDNA3 CB-2 (human). The cellswere grown in T-180 cell culture flasks under standard cell cultureconditions at 37° C. in a 5% CO₂ atmosphere. The cells were harvested bytrysinization and homogenized in a homogenization buffer (10 mM Tris,0.2 mM MgCl₂, 5 mM KCl, with protease inhibitors aprotinin, leupeptin,pepstatin A and bacitracin) and centrifuged (2000 g). The supernatantwas then centrifuged in 2M sucrose (31,300 g) to produce a semi-purifiedmembrane pellet. The pellet was resuspended in homogenization and storedat −80° C.

On the day of the assay, the pellet was thawed on ice and diluted inassay buffer (50 mM Tris-HCl, 5 mM MgCl₂, 2.5 mM EDTA, 0.5 mg/mL fattyacid free bovine serum albumin, pH 7.5). The diluted membrane pellet wasadded with buffer, either a test compound or vehicle standard and theradioligand [H]³⁺-CP-55,940 (0.2 nM) to the wells of a 96-wellpolypropylene plate. Non-specific binding was measured in wellscontaining WIN 55,212 (10 uM). The plate was covered and incubated for90 minutes at 30° C. The contents were then aspirated onto a PackardUnifilter GF/C filter bottom plate prewet with 0.5% polyethyleneimineThe wells of the polypropylene plate were rinsed and aspirated seventimes with a 0.9% saline-0.5% Tween 20 solution. The Unifilter plate wasdried, scintillation cocktail was added to each well and the countsrepresenting binding were quantitated in a TopCount scintillationcounter.

CB1 and CB2 Receptor Binding Results

For compounds tested, an IC₅₀ binding value was obtained from percentinhibition studies in which various test concentrations were used. Thebinding value was calculated by linear regression.

For compounds without an IC₅₀ binding value, the percent inhibition (%)was obtained at a test concentration of ⁽¹⁾ 10 μM, ⁽²⁾ 1 μM, ⁽³⁾ 0.2 μM,⁽⁴⁾ 0.003 μM, ⁽⁵⁾ represents an average value.

TABLE 1 Cannabinoid CB1 Receptor Binding IC₅₀ (μM) Cpd IC₅₀ 1 0.04 20.04, 0.5, 0.3, 0.2 2.1 3 ⁽¹⁾ 45% 4 0.06 5 ⁽¹⁾ 47% 6 0.3, ⁽²⁾ 86% 11 ⁽³⁾56% 12 0.008, ⁽³⁾ 89% 13 0.008, ⁽³⁾ 90% 14 ⁽³⁾ 50% 15 ⁽⁵⁾ 50% 16 ⁽⁵⁾ 59%17 0.01, ⁽³⁾ 86% 18 0.05, ⁽⁵⁾ 73% 19 ⁽⁵⁾ 65%

TABLE 2 Cannabinoid CB2 Receptor Binding IC₅₀ (μM) Cpd IC₅₀ 1 0.0001,0.00009 2 0.001, 0.006, 0.01, ⁽⁴⁾ 86% 3 0.02 4 ⁽⁴⁾ 74% 5 0.1 6 0.0006,0.0007, ⁽²⁾ 91% 11 ⁽³⁾ 30% 12 ⁽³⁾ 18% 13 ⁽³⁾ 11% 14 ⁽³⁾ 28% 15 ⁽⁵⁾ 25%16 ⁽⁵⁾ 20% 17 ⁽³⁾ 25% 18 ⁽⁵⁾ 44% 19 ⁽⁵⁾ 33%

Example 2 Functional Cell-Based Assay for CB1 or CB2 Agonist and InverseAgonist Effects on Intra-Cellular Adenylate Cyclase Activity

The CB1 and CB2 receptors are G-protein coupled receptors (GPCR), whichinfluence cell function via the Gi-protein. These receptors modulate theactivity of intracellular adenylate cyclase, which in turn produces theintracellular signal messenger cyclic-AMP (cAMP).

At baseline, or during non-ligand bound conditions, these receptors areconstitutively active and tonically suppress adenylate cyclase activity.The binding of an agonist causes further receptor activation andproduces additional suppression of adenylate cyclase activity. Thebinding of an inverse agonist inhibits the constitutive activity of thereceptors and results in an increase in adenylate cyclase activity.

By monitoring intracellular adenylate cyclase activity, the ability ofcompounds to act as agonists or inverse agonists can be determined

Assay

Test compounds were evaluated in SK-N-MC cells which, using standardtransfection procedures, were stably transfected with human cDNA forpcDNA3-CRE β-gal and pcDNA3 CB1 receptor (human) or pcDNA3 CB2 receptor(human). By expressing CRE β-gal, the cells produced β-galactosidase inresponse to CRE promoter activation by cAMP. Cells expressing CRE β-galand either the human CB1 or CB2 receptor will produce lessβ-galactosidase when treated with a CB1/CB2 agonist and will producemore β-galactosidase when treated with a CB1/CB2 inverse agonist.

Cell Growth

The cells were grown in 96-well plates under standard cell cultureconditions at 37° C. in a 5% CO₂ atmosphere. After 3 days, the media wasremoved and a test compound in media (wherein the media was supplementedwith 2 mM L-glutamine, 1M sodium pyruvate, 0.1% low fatty acid FBS(fetal bovine serum) and antibiotics) was added to the cell. The plateswere incubated for 30 minutes at 37° C. and the plate cells were thentreated with forskolin over a 4-6 hour period, then washed and lysed.The β-galactosidase activity was quantitated using commerciallyavailable kit reagents (Promega Corp. Madison, Wis.) and a Vmax PlateReader (Molecular Devices, Inc).

CB1 Receptor Mediated Change in CRE β-gal Expression

For cells expressing CRE β-gal and the CB1 receptor, CB1 agonistsreduced β-galactosidase activity in a dose-dependent manner and CB1inverse agonists increased β-galactosidase activity in a dose-dependentmanner.

The change in β-galactosidase activity was determined by setting avehicle treated cell's activity value at 100% and expressing theβ-galactosidase activity measured in a corresponding compound treatedcell as a percent of the vehicle treated cell activity.

CB1 Receptor Results

The EC₅₀ value for functional activity for compounds tested wascalculated by linear regression and was obtained from studies in whichvarying compound concentrations were used. Data provided for certaincompounds is represented by percent change (%) in functional activity ata single test concentration: ⁽¹⁾ 10 μM and ⁽²⁾ 1 μM.

TABLE 3 CB1 Receptor Functional Activity EC₅₀ (μM) Cpd EC₅₀ 1 ⁽¹⁾ −78% 2⁽²⁾ −71% 3  ⁽¹⁾ −6% 4 ⁽²⁾ −71% 5   ⁽¹⁾ 10% 12 0.01 13 0.002 17 0.04 180.02CB2 Receptor Mediated Change in CRE β-gal Expression

For cells expressing CRE β-gal and the CB2 receptor, CB2 agonistsreduced β-galactosidase activity in a dose-dependent manner and CB2inverse agonists increase β-galactosidase activity in a dose-dependentmanner.

The change in β-galactosidase activity was determined by setting avehicle treated cell's activity value at 100% and expressing theβ-galactosidase activity measured in a corresponding compound treatedcell as a percent of the vehicle treated cell activity.

CB2 Receptor Results

The EC₅₀ value for functional activity for compounds tested wascalculated by linear regression and was obtained from studies in whichvarying compound concentrations were used.

The value of 29% for Compound 5 represents change in functional activityand was obtained from a study in which one compound concentration wasused.

TABLE 4 CB2 Receptor Functional Activity EC₅₀ (μM) Cpd EC₅₀ 1 0.0016 20.0066 3 0.2 6 0.029

Example 4 Oil of Mustard Induced Colitis Model

In the distal colon, the oil of mustard colitis model is characterizedby a discontinuous pattern of mucosal epithelial damage, submucosaledema, infiltration of inflammatory cells (including macrophages,neutrophils and lymphocytes) into the mucosa and submucosa, increasedwet weight of the colon, shrinkage of the colon length, diarrhea andapparent inflammation (see, Kimball E. S., Palmer J. M., D′Andrea M. R.,Hornby P. J. and Wade P. R., Acute colitis induction by oil of mustardresults in later development of an IBS-like accelerated upper GI transitin mice, Am. J. Physiol. Gastrointest. Liver Physiol., 2005, 288:G1266-1273).

Colitis Induction

Male CD-1 mice (Charles River Laboratories, Kingston, N.C.)(9-11 weeksold) and fresh oil of mustard (OM) (allyl isothiocyanate, 98% purity,Sigma-Aldrich St. Louis, Mo.) were used.

The mice (9 per treatment group) were briefly anesthetized withketamine/xylasine (Sigma, St. Louis, Mo.) and a solution of 0.5% OM in30% ethanol (50 μL) was administered intracolonically (to a depth of 4cm) via syringe (equipped with a ball-tipped 22 G needle).

A test compound was orally administered one day prior to colitisinduction for assessing a prophylactic regimen or one day post-inductionfor assessing a therapeutic regimen. A test compound was orallyadministered daily thereafter. Two days after OM administration, thelast test compound dose was administered.

Three days after OM administration, the animals were sacrificed. Thecolons were resected, examined for signs of inflammation, weighed afterremoving fecal contents and the length from the aboral end of the cecumto the anus was measured. The fecal contents were examined for signs ofdiarrhea. The distal colon between the 1^(st) and the 4^(th) centimeterwas removed and placed in 10% neutral buffered formalin for histologicalanalysis.

Macroscopic Observations and Criteria

The macroscopic observations of colon inflammation (a measure of colondamage), colon weight and length and stool consistency and appearancewere assigned a score and used to evaluate colitis severity.

The four observation scores for each colon were combined, whereby acombined score of 0 represents a normal colon and a combined score of 15represents a maximally affected colon. Statistical analyses wereperformed in Graphpad Prism 4.0 using ANOVA.

0 1 2 3 4 Weight Score Weight Gain <5% 5-14% 15-24% 25-35% >35% LengthScore Shortening <5% 5-14% 15-24% 25-35% >35% Stool Score 0 1 2 3 FecalPellet normal (well- loosely- amorphous, diarrhea Formation formed)shaped, moist moist, sticky Damage Score 0 1 2 3 4 Inflammation noneobserved mild, moderate, severe, penetrating localized more widelyextensively ulcers, bloody erythema distributed distributed lesionserythema erythemaMicroscopic (Histological) Examination

Histological analyses of tissues consisted of staining paraffin-embeddedtissue sections with hematoxylin-eosin dye. The tissues were examinedusing light microscopy by an investigator who was blinded to the samplegroups.

Histological Observations and Criteria

The microscopic observations of epithelial damage, cellular infiltrationand damage or alteration of smooth muscle architecture (a measure ofmuscle damage) were assigned a score and used to evaluate colitisseverity.

The scores for each colon were combined, whereby a combined score of 0represents a normal colon and a combined score of 9 represents amaximally affected colon. Statistical analyses were performed inGraphpad Prism 4.0 using ANOVA.

Criteria and Observations

0 1 2 3 Epithelial Damage Score Epithelium intact ≦⅓ loss >⅓ to ⅔ >⅔loss Loss loss Cellular Infiltration Score Focal Areas of none 1-2focal >2 focal areas N/A Infiltration areas Infiltrated Cell none ≦⅓ ofentire >⅓ to ⅔ of ≧⅔ of Presence colon length entire colon entire lengthcolon length Architecture Score Muscle Damage no damage ≦⅓ of entire ≦⅔of entire ≧⅔ of (any evidence observed colon length colon length entireof edema, colon length hyperplasia or loss of architecture)Prophylactic and Therapeutic Colitis Treatment Regimen Results

The Macroscopic Score and Microscopic Score results for each treatmentgroup in the prophylactic and therapeutic regimens were each combinedinto a mean score and expressed as % inhibition of colitis (% Inh). Test(#) represents the number of experiments at each dose level.

TABLE 1 Prophylactic Regimen Cpd Dose (mg/kg) Test (#) % Inh (Macro) %Inh (Micro) 2 5 1 42.3 ± 12.6 74.4 ± 3.8

TABLE 2 Therapeutic Regimen Dose Cpd (mg/kg) Test (#) % Inh (Macro) Test(#) % Inh (Micro) 2 5 3 38.7 ± 9.1 1 66.0 ± 9.8

Example 5 Dextran Sulfate Sodium (DSS) Induced Colitis Model

In the distal colon, the DSS colitis model is characterized by adiscontinuous pattern of mucosal epithelial damage, infiltration ofinflammatory cells (including macrophages, neutrophils and lymphocytes)into the mucosa and submucosa, decreased wet weight of the colon,shrinkage of the colon length and diarrhea (see, Blumberg R. S.,Saubermann L. J. and Strober W., Animal models of mucosal inflammationand their relation to human inflammatory bowel disease, Current Opinionin Immunology, 1999, Vol. 11: 648-656; Egger B., Bajaj-Elliott M.,MacDonald T. T., Inglin R., Eysselein, V. E. and Buchler M. W.,Characterization of acute murine dextran sodium sulphate colitis:Cytokine profile and dose dependency, Digestion, 2000, Vol. 62: 240-248;Stevceva L., Pavli P., Husband A. J. and Doe, W. F., The inflammatoryinfiltrate in the acute stage of the dextran sulphate sodium inducedcolitis: B cell response differs depending on the percentage of DSS usedto induce it, BMC Clinical Pathology, 2001, Vol 1: 3-13; andDiaz-Granados, Howe K., Lu J. and McKay D. M., Dextran sulfatesodium-induced colonic histopathology, but not altered epithelial iontransport, is reduced by inhibition of phosphodiesterase activity, Amer.J. Pathology, 2000, Vol. 156: 2169-2177).

Colitis Induction

Female Balb/c mice (Taconic Farms, Germantown, N.Y.)(10-13 weeks old)were provided with a solution of 5% DSS (45 kD molecular weight, ICNchemicals, Newport, Calif.) in tap water ad libitum over a 7-day period.The DSS solution was replenished daily and the amount consumed wasmeasured.

The mice (10 per treatment group) were orally administered a testcompound on the day of colitis induction and then daily thereafter.

Six days after the initial DSS administration, the last test compounddose was administered.

Seven days after the initial DSS administration, the animals weresacrificed. The colons were resected, examined for signs ofinflammation, weighed after removing fecal contents and the length fromthe aboral end of the cecum to the anus was measured. The fecal contentswere examined for signs of diarrhea. The distal colon between the 1^(st)and the 4^(th) centimeter was removed and placed in 10% neutral bufferedformalin for histological analysis.

Macroscopic Observations and Criteria

The macroscopic observations of colon inflammation (a measure of colondamage), colon length and stool consistency and appearance were assigneda score and used to evaluate colitis severity.

The three observation scores for each colon were combined, whereby acombined score of 0 represents a normal colon and a combined score of 11represents a maximally affected colon. Statistical analyses wereperformed in Graphpad Prism 4.0 using ANOVA.

0 1 2 3 4 Weight Score Weight Gain <5% 5-14% 15-24% 25-35% >35% LengthScore Shortening <5% 5-14% 15-24% 25-35% >35% Stool Score 0 1 2 3 FecalPellet normal (well- loosely- amorphous, severe Formation formed)shaped, moist moist, sticky diarrhea Damage Score 0 1 2 3 4 Inflammationnone observed mild, moderate, severe, penetrating reddening more widelyextensively ulcers, bloody observed distributed distributed lesionsreddening reddeningMicroscopic (Histological) Examination

Histological analyses of tissues consisted of staining paraffin-embeddedtissue sections with hematoxylin-eosin dye. The tissues were examinedusing light microscopy by an investigator who was blinded to the samplegroups.

Histological Observations and Criteria

The microscopic observations of epithelial damage, cellular infiltrationand damage or alteration of smooth muscle architecture (a measure ofmuscle damage) were assigned a score and used to evaluate colitisseverity.

The scores for each colon were combined, whereby a combined score of 0represents a normal colon and a combined score of 9 represents amaximally affected colon. Statistical analyses were performed inGraphpad Prism 4.0 using ANOVA.

Criteria and Observations

0 1 2 3 Epithelial Damage Score Epithelium intact ≦⅓ loss >⅓ to ⅔ >⅔loss Loss loss Cellular Infiltration Score Focal Areas of none 1-2focal >2 focal areas N/A Infiltration areas Infiltrated Cell none ≦⅓ ofentire >⅓ to ⅔ of ≧⅔ of Presence colon length entire colon entire lengthcolon length Architecture Score Muscle Damage no damage ≦⅓ of entire ≦⅔of entire ≧⅔ of (any evidence observed colon length colon length entireof edema, colon length hyperplasia or loss of architecture)Colitis Treatment Regimen Results

The Macroscopic Score and Microscopic Score results for each treatmentgroup were each combined into a mean score and expressed as % inhibitionof colitis (% Inh). Test (#) represents the number of experiments ateach dose level. ND represents Not Determined.

TABLE 1 Cpd Dose (mg/kg) Test (#) % Inh (Macro) % Inh (Micro) 2 1 1 −4.3± 12.9 ND 2 5 1 21.9 ± 15.2 75.7 ± 8.9 2 10 1 50.5 ± 9.0  ND 2 20 1 31.6± 8.5  ND

It is to be understood that the preceding description of the inventionand various examples thereof have emphasized certain aspects. Numerousother equivalents not specifically elaborated on or discussed maynevertheless fall within the spirit and scope of the present inventionor the following claims and are intended to be included.

1. A method for treating a cannabinoid receptor mediated syndrome,disorder or disease in a subject in need thereof comprising the step ofadministering to the subject an effective amount of a compound offormula (1):

or a salt, isomer, prodrug, metabolite or polymorph thereof wherein thedashed lines between positions 2-3 and positions 3a-9a in formula (I)represent locations for each of two double bonds present when X₁R₁ ispresent; the dashed lines between positions 3-3a and positions 9a-1 informula (I) represent locations for each of two double bonds presentwhen X₂R₂ is present; the dashed line between position 9 and X₄R₄ informula (I) represents the location for a double bond; X₁ is absent orlower alkylene; X₂ is absent or lower alkylene; wherein only one of X₁R₁and X₂R₂ are present; X₃ is absent, lower alkylene, lower alkylidene or—NH—; when the dashed line between position 9 and X₄R₄ is absent, X₄ isabsent or lower alkylene; when the dashed line between position 9 andX₄R₄ is present, X₄ is absent; X₅ is absent or lower alkylene; R₁ isselected from hydrogen, alkyl (optionally substituted at one or morepositions by halogen, hydroxy or lower alkoxy), lower alkyl-sulfonyl,aryl, C₃-C₁₂ cycloalkyl or heterocyclyl, wherein aryl, C₃-C₁₂ cycloalkylor heterocyclyl is each optionally substituted at one or more positionsby halogen, aminosulfonyl, lower alkyl-aminosulfonyl, alkyl (optionallysubstituted at one or more positions by halogen, hydroxy or loweralkoxy), hydroxy or alkoxy (optionally substituted at one or morepositions by halogen or hydroxy); R₂ is selected from hydrogen, alkyl(optionally substituted at one or more positions by halogen, hydroxy orlower alkoxy), lower alkyl-sulfonyl, aryl, C₃-C₁₂ cycloalkyl orheterocyclyl, wherein aryl, C₃-C₁₂ cycloalkyl or heterocyclyl is eachoptionally substituted at one or more positions by halogen,aminosulfonyl, lower alkyl-aminosulfonyl, alkyl (optionally substitutedat one or more positions by halogen, hydroxy or lower alkoxy), hydroxyor alkoxy (optionally substituted at one or more positions by halogen orhydroxy); R₃ is —C(O)—Z₁(R₆), —SO₂—NR₇—Z₂(R₈) or —C(O)—NR₉—Z₃(R₁₀); whenthe dashed line between position 9 and X₄R₄ is absent, X₄ is absent orlower alkylene and R₄ is hydrogen, hydroxy, lower alkyl, lower alkoxy,halogen, aryl, C₃-C₁₂ cycloalkyl or heterocyclyl, wherein aryl, C₃-C₁₂cycloalkyl or heterocyclyl is each optionally substituted at one or morepositions by hydroxy, oxo, lower alkyl (optionally substituted at one ormore positions by halogen, hydroxy or lower alkoxy), lower alkoxy(optionally substituted at one or more positions by halogen or hydroxy)or halogen; when the dashed line between position 9 and X₄R₄ is present,X₄ is absent and R₄ is CH-aryl or CH-heterocyclyl, wherein aryl orheterocyclyl is each optionally substituted at one or more positions byhydroxy, oxo, lower alkyl, lower alkoxy or halogen; R₅ is absent,hydroxy, halogen, amino, aminoalkyl, alkyl (optionally substituted atone or more positions by halogen, hydroxy or lower alkoxy), alkoxy(optionally substituted at one or more positions by halogen or hydroxy),carboxy, carbonylalkoxy, carbamoyl, carbamoylalkyl, aryl, aryloxy,arylalkoxy or heterocyclyl; R₆ is aryl, C₃-C₁₂ cycloalkyl orheterocyclyl, wherein aryl, C₃-C₁₂ cycloalkyl or heterocyclyl is eachoptionally substituted by one or more hydroxy, oxo, halogen, amino,aminoalkyl, alkyl (optionally substituted at one or more positions byhalogen, hydroxy or lower alkoxy), alkoxy (optionally substituted at oneor more positions by halogen or hydroxy), carboxy, carbonylalkoxy,carbamoyl, carbamoylalkyl, aryl, aryloxy, arylalkoxy or heterocyclyl; R₇is hydrogen or lower alkyl; R₈ is aryl, C₃-C₁₂ cycloalkyl orheterocyclyl, wherein aryl, C₃-C₁₂ cycloalkyl or heterocyclyl is eachoptionally substituted by one or more hydroxy, oxo, halogen, amino,aminoalkyl, alkyl (optionally substituted at one or more positions byhalogen, hydroxy or lower alkoxy), alkoxy (optionally substituted at oneor more positions by halogen or hydroxy), carboxy, carbonylalkoxy,carbamoyl, carbamoylalkyl, aryl, aryloxy, arylalkoxy or heterocyclyl; R₉is hydrogen or lower alkyl; R₁₀ is aryl, C₃-C₁₂ cycloalkyl orheterocyclyl, wherein aryl, C₃-C₁₂ cycloalkyl or heterocyclyl is eachoptionally substituted by one or more hydroxy, oxo, halogen, amino,aminoalkyl, alkyl (optionally substituted at one or more positions byhalogen, hydroxy or lower alkoxy), alkoxy (optionally substituted at oneor more positions by halogen or hydroxy), carboxy, carbonylalkoxy,carbamoyl, carbamoylalkyl, aminosulfonyl, lower alkyl-aminosulfonyl,aryl, aryloxy, arylalkoxy or heterocyclyl; Z₁ and Z₂ is each absent oralkyl; and, Z₃ is absent, —NH—, —SO₂— or alkyl (wherein alkyl isoptionally substituted at one or more positions by halogen, hydroxy,lower alkyl, lower alkoxy, carboxy or carbonylalkoxy).
 2. The method ofclaim 1 wherein the cannabinoid receptor is a CB1 or CB2 receptor; and,the compound of Formula 1 is an agonist, antagonist or inverse-agonistof the receptor.
 3. The method of claim 1 wherein the syndrome, disorderor disease is related to appetite, metabolism, diabetes,glaucoma-associated intraocular pressure, social and mood disorders,seizures, substance abuse, learning, cognition or memory, organcontraction or muscle spasm, bowel disorders, respiratory disorders,locomotor activity or movement disorders, immune and inflammationdisorders, unregulated cell growth, pain management or neuroprotection.4. The method of claim 1 wherein the effective amount of the compound ofFormula 1 is from about 0.001 mg/kg/day to about 300 mg/kg/day.
 5. Themethod of claim 1 further comprising treating a CB1 receptorinverse-agonist mediated appetite related, obesity related or metabolismrelated syndrome, disorder or disease in a subject in need thereofcomprising the step of administering to the subject an effective amountof a CB1 inverse-agonist compound of Formula
 1. 6. The method of claim 5wherein the effective amount of the compound of Formula 1 is from about0.001 mg/kg/day to about 300 mg/kg/day.
 7. The method of claim 1 furthercomprising the step of administering to the subject a combinationproduct and/or therapy comprising an effective amount of a compound ofFormula 1 and a therapeutic agent.
 8. The method of claim 7 wherein thetherapeutic agent is an anticonvulsant or a contraceptive agent.
 9. Themethod of claim 8 wherein the anticonvulsant is topiramate, analogs oftopiramate, carbamazepine, valproic acid, lamotrigine, gabapentin,phenyloin and the like and mixtures or pharmaceutically acceptable saltsthereof.
 10. The method of claim 8 wherein the contraceptive agent is aprogestin-only contraceptive, a contraceptive having a progestincomponent and an estrogen component, or an oral contraceptive optionallyhaving a folic acid component.